U.S. patent application number 14/005659 was filed with the patent office on 2014-02-27 for indazole- and pyrrolopyridine-derivative and pharmaceutical use thereof.
The applicant listed for this patent is Nana Goto, Junya Ikeda, Masato Iwata, Kazuhiro Mizuno, Takanori Nakamura, Hiromichi Otaka. Invention is credited to Nana Goto, Junya Ikeda, Masato Iwata, Kazuhiro Mizuno, Takanori Nakamura, Hiromichi Otaka.
Application Number | 20140057895 14/005659 |
Document ID | / |
Family ID | 47296200 |
Filed Date | 2014-02-27 |
United States Patent
Application |
20140057895 |
Kind Code |
A1 |
Mizuno; Kazuhiro ; et
al. |
February 27, 2014 |
INDAZOLE- AND PYRROLOPYRIDINE-DERIVATIVE AND PHARMACEUTICAL USE
THEREOF
Abstract
The present invention relates to a novel indazole- or
pyrrolopyridine-derivative comprising a 5 membered heterocyclic
substituent at 1 position thereof which has an agonistic action or
a partial agonistic action against serotonin-4 receptor, and a
pharmaceutical composition comprising the same.
Inventors: |
Mizuno; Kazuhiro;
(Osaka-shi, JP) ; Ikeda; Junya; (Osaka-shi,
JP) ; Nakamura; Takanori; (Osaka-shi, JP) ;
Iwata; Masato; (Osaka-shi, JP) ; Otaka;
Hiromichi; (Suita-shi, JP) ; Goto; Nana;
(Suita-shi, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Mizuno; Kazuhiro
Ikeda; Junya
Nakamura; Takanori
Iwata; Masato
Otaka; Hiromichi
Goto; Nana |
Osaka-shi
Osaka-shi
Osaka-shi
Osaka-shi
Suita-shi
Suita-shi |
|
JP
JP
JP
JP
JP
JP |
|
|
Family ID: |
47296200 |
Appl. No.: |
14/005659 |
Filed: |
June 6, 2012 |
PCT Filed: |
June 6, 2012 |
PCT NO: |
PCT/JP2012/065052 |
371 Date: |
October 16, 2013 |
Current U.S.
Class: |
514/210.21 ;
514/234.5; 514/300; 514/316; 514/322; 514/364; 544/138; 546/113;
546/187; 546/199; 548/133 |
Current CPC
Class: |
A61P 25/22 20180101;
A61P 1/00 20180101; A61P 1/14 20180101; A61P 13/02 20180101; A61P
43/00 20180101; A61P 25/28 20180101; A61P 1/08 20180101; A61P 13/08
20180101; C07D 471/04 20130101; A61P 1/10 20180101; A61P 25/24
20180101; C07D 413/14 20130101; A61P 1/04 20180101; C07D 417/14
20130101; A61P 17/00 20180101; C07D 417/04 20130101; C07D 413/04
20130101; C07D 471/08 20130101; A61P 25/18 20180101 |
Class at
Publication: |
514/210.21 ;
546/199; 514/322; 546/187; 514/316; 544/138; 514/234.5; 548/133;
514/364; 546/113; 514/300 |
International
Class: |
C07D 471/04 20060101
C07D471/04; C07D 413/04 20060101 C07D413/04; C07D 417/14 20060101
C07D417/14; C07D 413/14 20060101 C07D413/14 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 7, 2011 |
JP |
2011-127688 |
Claims
1. A compound of Formula (1): ##STR00668## or a pharmaceutically
acceptable salt thereof wherein A is the following Formula (A-1),
Formula (A-2), Formula (A-3), or Formula (A-4): ##STR00669##
wherein l is an integer of 0 to 4, m is an integer of 0 to 2, n is
an integer of 0 to 2, o and p are independently an integer of 0 or
1, q is an integer of 0 to 5, (A-1) to (A-4) may be independently
and optionally substituted with one or more substituents
independently-selected from the group consisting of C.sub.1-6 alkyl
group, C.sub.2-6 alkenyl group, C.sub.2-6 alkynyl group, hydroxy
group, C.sub.1-6 alkoxy group, and halogen atom at each
substitutable position thereof, B is the following Formula (B-1),
Formula (B-2), or Formula (B-3): ##STR00670## wherein (B-2) and
(B-3) may optionally include an unsaturated bond(s) at an
acceptable position(s) of the ring, provided that D is absent when
B is (B-1), R.sup.8, R.sup.9 and D are independently a group
selected from the group consisting of the following (1) and (2):
(1) hydrogen atom, an optionally-substituted C.sub.1-6 alkyl group,
an optionally-substituted C.sub.3-6 alkenyl group, an
optionally-substituted C.sub.3-6 alkynyl group, an
optionally-substituted C.sub.3-8 monocyclic, C.sub.7-10 bicyclic or
C.sub.7-12 tricyclic cycloalkyl group, and an
optionally-substituted C.sub.5-8 monocyclic or C.sub.7-10 bicyclic
cycloalkenyl group wherein the C.sub.1-6 alkyl group, C.sub.3-6
alkenyl group, C.sub.3-6 alkynyl group, C.sub.3-8 monocyclic,
C.sub.7-10 bicyclic or C.sub.7-12 tricyclic cycloalkyl group, and
C.sub.5-8 monocyclic or C.sub.7-10 bicyclic cycloalkenyl group may
be independently and optionally substituted with one or more
substituents independently-selected from the group consisting of
C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy group,
C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy group, cyano group,
oxo group, aryl group, heteroaryl group, aryloxy group, C.sub.2-6
alkanoyl group, phenacyl group, and halogen atom at each
substitutable position thereof; (2) --(CH.sub.2).sub.u--R.sup.12
wherein u is an integer of 0 to 4 provided that when u is an
integer of 1 to 4, the alkylene chain may be optionally substituted
with one or more substituents independently-selected from the group
consisting of C.sub.1-6 alkyl group, C.sub.2-6 alkenyl group,
C.sub.2-6 alkynyl group, hydroxy group, C.sub.1-6 alkoxy group, oxo
group, and halogen atom, R.sup.12 is the following Formula
(R.sup.12-1), Formula (R.sup.12-2), Formula (R.sup.12-3), Formula
(R.sup.12-4), Formula (R.sup.12-5), Formula (R.sup.12-6), Formula
(R.sup.12-7), or Formula (R.sup.12-8): ##STR00671## wherein
R.sup.13 is a group selected from the group consisting of the
following (1) to (5): (1) hydrogen atom and formyl group; (2) an
optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.3-6 alkenyl group, an
optionally-substituted C.sub.3-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, and an
optionally-substituted C.sub.5-8 cycloalkenyl group wherein the
C.sub.1-6 alkyl group, C.sub.3-6 alkenyl group, C.sub.3-6 alkynyl
group, C.sub.3-8 cycloalkyl group, and C.sub.5-8 cycloalkenyl group
may be independently and optionally substituted with one or more
substituents independently-selected from the group consisting of
C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy group,
C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy group, cyano group,
oxo group, and halogen atom at each substitutable position thereof;
(3) --COR.sup.16, --CSR.sup.16, --SO.sub.2R.sup.16,
--CO--COR.sup.16, --COOR.sup.16, and --CO--COOR.sup.16 wherein
R.sup.16 is an optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.3-6 alkenyl group, an
optionally-substituted C.sub.3-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted C.sub.5-8 cycloalkenyl group, an
optionally-substituted aryl group, an optionally-substituted
heteroaryl group, an optionally-substituted 5- to 9-membered
monocyclic or 7- to 10-membered bicyclic non-aromatic unsaturated
heterocyclic group (wherein the binding site is any one carbon atom
in the heterocyclic ring), or an optionally-substituted 4- to
9-membered monocyclic or 7- to 10-membered bicyclic saturated
heterocyclic group (wherein the binding site is any one carbon atom
in the heterocyclic ring), wherein the C.sub.1-6 alkyl group,
C.sub.3-6 alkenyl group, C.sub.3-6 alkynyl group, C.sub.3-8
cycloalkyl group, C.sub.5-8 cycloalkenyl group, 5- to 9-membered
monocyclic or 7- to 10-membered bicyclic non-aromatic unsaturated
heterocyclic group, and 4- to 9-membered monocyclic or 7- to
10-membered bicyclic saturated heterocyclic group may be
independently and optionally substituted with one or more
substituents independently-selected from the group consisting of
C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy group,
C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy group, cyano group,
oxo group, aryl group, heteroaryl group, and halogen atom at each
substitutable position thereof; and the aryl group and heteroaryl
group may be independently and optionally substituted with one or
more substituents independently-selected from the group consisting
of halogen atom, hydroxy group, C.sub.1-4 alkyl group, C.sub.1-4
alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy
group, cyano group, nitro group, C.sub.2-6 alkanoyl group, and an
optionally-substituted amino group at each substitutable position
thereof; (4) --CONR.sup.17--OR.sup.18 wherein R.sup.17 and R.sup.18
are independently hydrogen atom, C.sub.1-6 alkyl group, C.sub.3-6
alkenyl group or C.sub.3-6 alkynyl group; (5)
--CONR.sup.19R.sup.20, --CSNR.sup.19R.sup.20 and
--SO.sub.2NR.sup.19R.sup.20 wherein R.sup.19 and R.sup.20 are
independently hydrogen atom or any group defined in the said
R.sup.16, or R.sup.19 and R.sup.20 may be taken together with the
adjacent nitrogen atom to form a saturated or unsaturated 4- to
8-membered monocyclic nitrogen-containing heterocyclic group
comprising additional 0 to 2 heteroatoms independently-selected
from the group consisting of 1 to 2 nitrogen atoms, 1 oxygen atom
and 1 sulfur atom wherein the heterocyclic group may be optionally
substituted with one or more substituents independently-selected
from the group consisting of C.sub.1-4 alkyl group, hydroxy group,
C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4
haloalkoxy group, cyano group, oxo group, and halogen atom at each
substitutable position thereof, R.sup.14 and R.sup.15 are
independently hydrogen atom, an optionally-substituted C.sub.1-6
alkyl group, an optionally-substituted C.sub.3-6 alkenyl group, an
optionally-substituted C.sub.3-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted C.sub.5-8 cycloalkenyl group, an
optionally-substituted aryl group, an optionally-substituted
heteroaryl group, an optionally-substituted 5- to 9-membered
monocyclic or 7- to 10-membered bicyclic non-aromatic unsaturated
heterocyclic group (which is attached to the adjacent nitrogen atom
via any one carbon atom in the heterocyclic group), an
optionally-substituted 4- to 9-membered monocyclic or 7- to
10-membered bicyclic saturated heterocyclic group (which is
attached to the adjacent nitrogen atom via any one carbon atom in
the heterocyclic group), C.sub.2-6 alkanoyl group, C.sub.1-6
alkoxycarbonyl group, carbamoyl group, sulfamoyl group, or
C.sub.1-6 alkylsulfonyl group, wherein the C.sub.1-6 alkyl group,
C.sub.3-6 alkenyl group, C.sub.3-6 alkynyl group, C.sub.3-8
cycloalkyl group, C.sub.5-8 cycloalkenyl group, 5- to 9-membered
monocyclic or 7- to 10-membered bicyclic non-aromatic unsaturated
heterocyclic group, 4- to 9-membered monocyclic or 7- to
10-membered bicyclic saturated heterocyclic group, C.sub.2-6
alkanoyl group, C.sub.1-6 alkoxycarbonyl group, and C.sub.1-6
alkylsulfonyl group may be independently and optionally substituted
with one or more substituents independently-selected from the group
consisting of C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4
alkoxy group, cyano group, oxo group, aryl group, heteroaryl group,
and halogen atom at each substitutable position thereof; and the
aryl group and heteroaryl group may be independently and optionally
substituted with one or more substituents independently-selected
from the group consisting of halogen atom, hydroxy group, C.sub.1-4
alkyl group, C.sub.1-4 alkoxy group, cyano group, nitro group,
C.sub.2-6 alkanoyl group, and an optionally-substituted amino group
at each substitutable position thereof, or R.sup.14 and R.sup.15
may be taken together with the adjacent nitrogen atom to form a
saturated or unsaturated 4- to 9-membered monocyclic or 7- to
10-membered bicyclic nitrogen-containing heterocyclic group
comprising additional 0 to 2 heteroatoms independently-selected
from the group consisting of 1 to 2 nitrogen atoms, 1 oxygen atom
and 1 sulfur atom wherein the heterocyclic group may be optionally
substituted with one or more substituents independently-selected
from the group consisting of C.sub.1-4 alkyl group, hydroxy group,
C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4
haloalkoxy group, cyano group, oxo group, and halogen atom at each
substitutable position thereof, (R.sup.12-1) to (R.sup.12-4) may
optionally include an unsaturated bond(s) at an acceptable
position(s) of the ring, R.sup.8' and R.sup.9' are independently
hydrogen atom, an optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.3-6 alkenyl group, an
optionally-substituted C.sub.3-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted C.sub.5-8 cycloalkenyl group, an
optionally-substituted aryl group, an optionally-substituted
heteroaryl group, an optionally-substituted 5- to 9-membered
monocyclic or 7- to 10-membered bicyclic non-aromatic unsaturated
heterocyclic group (which is attached to the adjacent nitrogen atom
via any one carbon atom in the heterocyclic group), or an
optionally-substituted 4- to 9-membered monocyclic or 7- to
10-membered bicyclic saturated heterocyclic group (which is
attached to the adjacent nitrogen atom via any one carbon atom in
the heterocyclic group), wherein the C.sub.1-6 alkyl group,
C.sub.3-6 alkenyl group, C.sub.3-6 alkynyl group, C.sub.3-8
cycloalkyl group, C.sub.5-8 cycloalkenyl group, 5- to 9-membered
monocyclic or 7- to 10-membered bicyclic non-aromatic unsaturated
heterocyclic group, and 4- to 9-membered monocyclic or 7- to
10-membered bicyclic saturated heterocyclic group may be
independently and optionally substituted with one or more
substituents independently-selected from the group consisting of
C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy group,
C.sub.1-4 haloalkoxy group, cyano group, oxo group, aryl group,
heteroaryl group, aryloxy group, C.sub.2-6 alkanoyl group, phenacyl
group, and halogen atom at each substitutable position thereof; and
the aryl group and heteroaryl group may be independently and
optionally substituted with one or more substituents
independently-selected from the group consisting of halogen atom,
hydroxy group, C.sub.1-4 alkyl group, C.sub.1-4 alkoxy group,
C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy group, cyano group,
nitro group, C.sub.2-6 alkanoyl group, and an
optionally-substituted amino group at each substitutable position
thereof, or a pair of R.sup.8 and R.sup.9, and a pair of R.sup.8
and R.sup.9' may be independently taken together with the adjacent
nitrogen atom to form a saturated or unsaturated 4- to 9-membered
monocyclic or 7- to 10-membered bicyclic nitrogen-containing
heterocyclic group comprising additional 0 to 2 heteroatoms
independently-selected from the group consisting of 1 to 2 nitrogen
atoms, 1 oxygen atom and 1 sulfur atom wherein the
nitrogen-containing heterocyclic group may be optionally
substituted with one or more substituents independently-selected
from the group consisting of C.sub.1-4 alkyl group, hydroxy group,
C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4
haloalkoxy group, cyano group, oxo group, and halogen atom at each
substitutable position thereof, R.sup.10, R.sup.10', R.sup.11 and
R.sup.11' are independently hydrogen atom, halogen atom, hydroxy
group, an optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.2-6 alkenyl group, an
optionally-substituted C.sub.2-6 alkynyl group, an
optionally-substituted C.sub.1-6 alkoxy group, cyano group, or an
oxo group, wherein the C.sub.1-6 alkyl group, C.sub.2-6 alkenyl
group, C.sub.2-6 alkynyl group, and C.sub.1-6 alkoxy group may be
independently and optionally substituted with one or more
substituents independently-selected from the group consisting of
C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy group,
C.sub.1-4 haloalkoxy group, cyano group, oxo group, aryl group,
heteroaryl group, aryloxy group, C.sub.2-6 alkanoyl group, phenacyl
group, and halogen atom at each substitutable position thereof, or
a pair of R.sup.10 and R.sup.11, and a pair of R.sup.10' and
R.sup.11' may be independently taken together to form an
optionally-substituted saturated or unsaturated 3- to 8-membered
ring that may comprise 1 oxygen atom, which may be a bicyclic or a
spiro compound with the ring to which the pair of R.sup.10 and
R.sup.11, or R.sup.10' and R.sup.11' is attached, wherein the
saturated or unsaturated 3- to 8-membered ring may be optionally
substituted with one or more substituents independently-selected
from the group consisting of C.sub.1-4 alkyl group, hydroxy group,
C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4
haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl
group, aryloxy group, C.sub.2-6 alkanoyl group, phenacyl group, and
halogen atom at each substitutable position thereof, r and r' are
independently an integer of 0 to 3, s and s' are independently an
integer of 0 to 3, t and t' are independently 1 or 2, v is an
integer of 0 to 2, provided that not both r and s are 0, V is
nitrogen atom or C--R.sup.1 wherein R.sup.1 is hydrogen atom,
halogen atom, an optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.2-6 alkenyl group, an
optionally-substituted C.sub.2-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted C.sub.5-8 cycloalkenyl group, an
optionally-substituted aryl group, or an optionally-substituted
heteroaryl group, wherein the C.sub.1-6 alkyl group, C.sub.2-6
alkenyl group, C.sub.2-6 alkynyl group, C.sub.3-8 cycloalkyl group,
and C.sub.5-8 cycloalkenyl group may be independently and
optionally substituted with one or more substituents
independently-selected from the group consisting of C.sub.1-4 alkyl
group, hydroxy group, C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl
group, C.sub.1-4 haloalkoxy group, cyano group, oxo group, aryl
group, heteroaryl group, aryloxy group, C.sub.2-6 alkanoyl group,
phenacyl group, and halogen atom at each substitutable position
thereof; and the aryl group and heteroaryl group may be
independently and optionally substituted with one or more
substituents independently-selected from the group consisting of
halogen atom, hydroxy group, C
.sub.1-4 alkyl group, C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl
group, C.sub.1-4 haloalkoxy group, cyano group, nitro group,
C.sub.2-6 alkanoyl group, and an optionally-substituted amino group
at each substitutable position thereof, W is nitrogen atom or
C--R.sup.2 wherein R.sup.2 is hydrogen atom, halogen atom, hydroxy
group, an optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.2-6 alkenyl group, an
optionally-substituted C.sub.2-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted C.sub.5-8 cycloalkenyl group, an
optionally-substituted C.sub.1-6 alkoxy group, an
optionally-substituted C.sub.1-4 haloalkyl group, an
optionally-substituted C.sub.1-4 haloalkoxy group, cyano group,
nitro group, an optionally-substituted aryl group, an
optionally-substituted heteroaryl group, or an
optionally-substituted amino group, wherein the C.sub.1-6 alkyl
group, C.sub.2-6 alkenyl group, C.sub.2-6 alkynyl group, C.sub.3-8
cycloalkyl group, C.sub.5-8 cycloalkenyl group, C.sub.1-6 alkoxy
group, C.sub.1-4 haloalkyl group, and C.sub.1-4 haloalkoxy group
may be independently and optionally substituted with one or more
substituents independently-selected from the group consisting of
C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy group,
C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy group, cyano group,
oxo group, aryl group, heteroaryl group, aryloxy group, C.sub.2-6
alkanoyl group, phenacyl group, and halogen atom at each
substitutable position thereof; and the aryl group and heteroaryl
group may be independently and optionally substituted with one or
more substituents independently-selected from the group consisting
of halogen atom, hydroxy group, C.sub.1-4 alkyl group, C.sub.1-4
alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy
group, cyano group, nitro group, C.sub.2-6 alkanoyl group, and an
optionally-substituted amino group at each substitutable position
thereof, provided that when V is C--R.sup.1, W is nitrogen atom,
and when V is nitrogen atom, W is C--R.sup.2, U is carbon atom or
nitrogen atom, X, Y and Z are independently selected from the group
consisting of oxygen atom, nitrogen atom, sulfur atom and carbon
atom, provided that at least one of X, Y and Z is oxygen atom,
sulfur atom, or nitrogen atom, provided that thiazole and oxazole
rings are excluded from the 5-membered heteroaryl ring comprising
X, Y and Z, R.sup.3 is hydrogen atom, halogen atom, an
optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.2-6 alkenyl group, an
optionally-substituted C.sub.2-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted C.sub.5-8 cycloalkenyl group, an
optionally-substituted C.sub.1-6 alkoxy group, an
optionally-substituted C.sub.1-4 haloalkyl group, an
optionally-substituted C.sub.1-4 haloalkoxy group, cyano group,
nitro group, an optionally-substituted aryl group, an
optionally-substituted heteroaryl group, an optionally-substituted
5- to 9-membered monocyclic or 7- to 10-membered bicyclic
non-aromatic unsaturated heterocyclic group, or an
optionally-substituted 4- to 9-membered monocyclic or 7- to
10-membered bicyclic saturated heterocyclic group, wherein the
C.sub.1-6 alkyl group, C.sub.2-6 alkenyl group, C.sub.2-6 alkynyl
group, C.sub.3-8 cycloalkyl group, C.sub.5-8 cycloalkenyl group,
C.sub.1-6 alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4
haloalkoxy group, 5- to 9-membered monocyclic or 7- to 10-membered
bicyclic non-aromatic unsaturated heterocyclic group, and 4- to
9-membered monocyclic or 7- to 10-membered bicyclic saturated
heterocyclic group may be independently and optionally substituted
with one or more substituents independently-selected from the group
consisting of C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4
alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy
group, cyano group, oxo group, aryl group, heteroaryl group,
aryloxy group, C.sub.2-6 alkanoyl group, phenacyl group, and
halogen atom at each substitutable position thereof; and the aryl
group and heteroaryl group may be independently and optionally
substituted with one or more substituents independently-selected
from the group consisting of halogen atom, hydroxy group, C.sub.1-4
alkyl group, C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl group,
C.sub.1-4 haloalkoxy group, cyano group, nitro group, C.sub.2-6
alkanoyl group, and an optionally-substituted amino group at each
substitutable position thereof, R.sup.4 is hydrogen atom, halogen
atom, hydroxy group, an optionally-substituted C.sub.1-6 alkyl
group, an optionally-substituted C.sub.2-6 alkenyl group, an
optionally-substituted C.sub.2-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted C.sub.5-8 cycloalkenyl group, an
optionally-substituted C.sub.1-6 alkoxy group, an
optionally-substituted C.sub.1-4 haloalkyl group, an
optionally-substituted C.sub.1-4 haloalkoxy group, cyano group,
nitro group, an optionally-substituted aryl group, an
optionally-substituted heteroaryl group, or an
optionally-substituted amino group, wherein the C.sub.1-6 alkyl
group, C.sub.2-6 alkenyl group, C.sub.2-6 alkynyl group, C.sub.3-8
cycloalkyl group, C.sub.5-8 cycloalkenyl group, C.sub.1-6 alkoxy
group, C.sub.1-4 haloalkyl group, and C.sub.1-4 haloalkoxy group
may be independently and optionally substituted with one or more
substituents independently-selected from the group consisting of
C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy group,
C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy group, cyano group,
oxo group, aryl group, heteroaryl group, aryloxy group, C.sub.2-6
alkanoyl group, phenacyl group, and halogen atom at each
substitutable position thereof; and the aryl group and heteroaryl
group may be independently and optionally substituted with one or
more substituents independently-selected from the group consisting
of halogen atom, hydroxy group, C.sub.1-4 alkyl group, C.sub.1-4
alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy
group, cyano group, nitro group, C.sub.2-6 alkanoyl group, and an
optionally-substituted amino group at each substitutable position
thereof, or R.sup.3 and R.sup.4 may be taken together to form a
saturated or unsaturated 6- to 9-membered ring optionally
comprising 1 oxygen atom wherein the ring may be optionally
substituted with one or more substituents independently-selected
from the group consisting of C.sub.1-4 alkyl group, hydroxy group,
C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4
haloalkoxy group, cyano group, oxo group, and halogen atom at each
substitutable position thereof, and R.sup.5 and R.sup.6 are
independently hydrogen atom, halogen atom, hydroxy group, an
optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.2-6 alkenyl group, an
optionally-substituted C.sub.2-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted C.sub.5-8 cycloalkenyl group, an
optionally-substituted C.sub.1-6 alkoxy group, an
optionally-substituted C.sub.1-4 haloalkyl group, an
optionally-substituted C.sub.1-4 haloalkoxy group, cyano group,
nitro group, an optionally-substituted aryl group, an
optionally-substituted heteroaryl group, or an
optionally-substituted amino group, wherein the C.sub.1-6 alkyl
group, C.sub.2-6 alkenyl group, C.sub.2-6 alkynyl group, C.sub.3-8
cycloalkyl group, C.sub.5-8 cycloalkenyl group, C.sub.1-6 alkoxy
group, C.sub.1-4 haloalkyl group, and C.sub.1-4 haloalkoxy group
may be independently and optionally substituted with one or more
substituents independently-selected from the group consisting of
C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy group,
C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy group, cyano group,
oxo group, aryl group, heteroaryl group, aryloxy group, C.sub.2-6
alkanoyl group, phenacyl group, and halogen atom at each
substitutable position thereof; and the aryl group and heteroaryl
group may be independently and optionally substituted with one or
more substituents independently-selected from the group consisting
of halogen atom, hydroxy group, C.sub.1-4 alkyl group, C.sub.1-4
alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy
group, cyano group, nitro group, C.sub.2-6 alkanoyl group, and an
optionally-substituted amino group at each substitutable position
thereof.
2. The compound of claim 1 or a pharmaceutically acceptable salt
thereof wherein V is nitrogen atom and W is C--R.sup.2.
3. The compound of claim 1 or a pharmaceutically acceptable salt
thereof wherein R.sup.3 is hydrogen atom, halogen atom, an
optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.2-6 alkenyl group, an
optionally-substituted C.sub.2-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, or an
optionally-substituted C.sub.5-8 cycloalkenyl group.
4. The compound of claim 1 or a pharmaceutically acceptable salt
thereof wherein R.sup.4 and R.sup.5 are hydrogen atom, and R.sup.2
and R.sup.6 are independently hydrogen atom, halogen atom, an
optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.1-6 alkoxy group, an
optionally-substituted C.sub.1-4 haloalkyl group, an
optionally-substituted C.sub.1-4 haloalkoxy group, or cyano
group.
5. The compound of claim 1 or a pharmaceutically acceptable salt
thereof wherein U is carbon atom.
6. The compound of claim 1 or a pharmaceutically acceptable salt
thereof wherein X is nitrogen atom, Y is oxygen atom, and Z is
nitrogen atom.
7. The compound of claim 1 or a pharmaceutically acceptable salt
thereof wherein A is (A-1), and 1 is an integer of 0 or 1.
8. The compound of claim 1 or a pharmaceutically acceptable salt
thereof wherein B is (B-2), s is an integer of 1, and r is an
integer of 1 or 2.
9. The compound of claim 1 which has a chemical structure of
Formula (12): ##STR00672## or a pharmaceutically acceptable salt
thereof.
10. The compound of claim 1 or a pharmaceutically acceptable salt
thereof wherein D is hydrogen atom, an optionally-substituted
C.sub.1-6 alkyl group, or an optionally-substituted C.sub.3-8
monocyclic, C.sub.7-10 bicyclic or C.sub.7-12 tricyclic cycloalkyl
group.
11. The compound of claim 1 or a pharmaceutically acceptable salt
thereof wherein D is --(CH.sub.2).sub.u--R.sup.12, and R.sup.12 is
Formula (R.sup.12-3).
12. The compound of claim 1 or a pharmaceutically acceptable salt
thereof wherein D is --(CH.sub.2).sub.u--R.sup.12, and R.sup.12 is
Formula (R.sup.12-1).
13. The compound of claim 1 or a pharmaceutically acceptable salt
thereof wherein A is (A-3), o is an integer of 0, p is an integer
of 0, q is an integer of either 1 or 3, and B is (B-1).
14. The compound of claim 1 which has a chemical structure of
Formula (13): ##STR00673## or a pharmaceutically acceptable salt
thereof.
15. The compound of claim 1 which is selected from the group
consisting of the following compounds or a pharmaceutically
acceptable salt thereof: (01)
1-{5-[1-(3-methoxypropyl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}-3-(pr-
opan-2-yl)-1H-indazole, (02)
3-ethyl-1-{5-[1-(3-methoxypropyl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}-1H-
-indazole, (03)
3-cyclopropyl-1-{5-[1-(3-methoxypropyl)piperidin-4-yl]-1,2,4-oxadiazol-3--
yl}-1H-indazole, (04)
3-ethyl-6-fluoro-1-{5-[1-(3-methoxypropyl)piperidin-4-yl]-1,2,4-oxadiazol-
-3-yl}-1H-indazole, (05)
3-ethyl-7-fluoro-1-{5-[1-(3-methoxypropyl)piperidin-4-yl]-1,2,4-oxadiazol-
-3-yl}-1H-indazole, (06)
1-{5-[1-(2-methylpropyl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}-3-(propan-2-
-yl)-1H-indazole, (07)
1-{5-[1-(butan-2-yl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}-3-ethyl-1H-inda-
zole, (08)
1-{5-[1-(butan-2-yl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}-3-cyc-
lopropyl-1H-indazole, (09)
3-ethyl-1-{5-[1-(2-methylpropyl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}-1H--
indazole, (10)
1-{5-[1-(cyclopropylmethyl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}-3-ethyl--
1H-indazole, (11)
1-{5-[1-(butan-2-yl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}-3-cyclobutyl-1H-
-indazole, (12)
3-cyclobutyl-1-{5-[1-(2-methylpropyl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl-
}-1H-indazole, (13)
3-(propan-2-yl)-1-[5-(1-propylpiperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-in-
dazole, (14)
3-ethyl-6-fluoro-1-(5-{1-[2-(tetrahydrofuran-2-yl)ethyl]piperidin-4-yl}-1-
,2,4-oxadiazol-3-yl)-1H-indazole, (15)
3-ethyl-1-{5-[1-(tetrahydrofuran-2-ylmethyl)piperidin-4-yl]-1,2,4-oxadiaz-
ol-3-yl}-1H-indazole, (16)
3-ethyl-6-fluoro-1-{5-[1-(tetrahydro-2H-pyran-4-ylmethyl)piperidin-4-yl]--
1,2,4-oxadiazol-3-yl}-1H-indazole, (17)
3-ethyl-6-fluoro-1-(5-{1-[2-(tetrahydro-2H-pyran-4-yl)ethyl]piperidin-4-y-
l}-1,2,4-oxadiazol-3-yl)-1H-indazole, (18)
3-ethyl-6-fluoro-1-{5-[1-(tetrahydrofuran-3-yl)piperidin-4-yl]-1,2,4-oxad-
iazol-3-yl}-1H-indazole, (19)
3-ethyl-6-fluoro-1-{5-[1-(propan-2-yl)piperidin-4-yl]-1,2,4-oxadiazol-3-y-
l}-1H-indazole, (20) methyl
4-({4-[3-(3-ethyl-6-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidi-
n-1-yl}methyl)piperidine-1-carboxylate, (21) methyl
(2S)-2-({4-[3-(3-ethyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidin-1--
yl}methyl)pyrrolidine-1-carboxylate, (22) 2-fluoroethyl
(2S)-2-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]pip-
eridin-1-yl}methyl)pyrrolidine-1-carboxylate, (23) 2-fluoroethyl
(3S)-3-({4-[3-(3-ethyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidin-1--
yl}methyl)pyrrolidine-1-carboxylate, (24)
1-[3-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piper-
idin-1-yl}methyl)azetidin-1-yl]-2-methoxyethanone, (25)
1-{4-[3-(3-ethyl-6-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-1,4'-bip-
iperidin-1'-yl}ethanone, (26)
1-{4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-1,4'-bip-
iperidin-1'-yl}ethanone, (27) methyl
4-[3-(3-ethyl-6-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-1,4'-bipipe-
ridine-1'-carboxylate, (28)
1-(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}--
1,4'-bipiperidin-1'-yl)ethanone, (29)
1-(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}--
1,4'-bipiperidin-1'-yl)-2-hydroxyethanone, (30) methyl
4-{3-[3-(3-ethyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]azetidin-1-yl}pipe-
ridine-1-carboxylate, (31)
3-{4-[3-(3-ethyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}pro-
pan-1-ol, (32)
cis-N-ethyl-3-[3-(3-ethyl-6-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-
cyclobutanamine, (33)
1-[(3R)-3-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-
piperidin-1-yl}methyl)pyrrolidin-1-yl]ethanone, (34)
1-[(3R)-3-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-
piperidin-1-yl}methyl)pyrrolidin-1-yl]-2-methoxyethanone, (35)
1-[(3R)-3-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-
piperidin-1-yl}methyl)pyrrolidin-1-yl]-2-hydroxyethanone, (36)
1-{4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-1,4'-bip-
iperidin-1'-yl}-2-hydroxyethanone, (37)
1-{4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-1,4'-bip-
iperidin-1'-yl}-2-methoxyethanone, (38)
4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-1'-(methyls-
ulfonyl)-1,4'-bipiperidine, (39)
1-(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}--
1,4'-bipiperidin-1'-yl)-2-methoxyethanone, (40)
1-[(3S)-3-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-
piperidin-1-yl}methyl)pyrrolidin-1-yl]ethanone, (41)
1-[(3S)-3-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-
piperidin-1-yl}methyl)pyrrolidin-1-yl]-2-methoxyethanone, (42)
3-ethyl-7-fluoro-1-[5-(1-{[(3S)-1-(methylsulfonyl)pyrrolidin-3-yl]methyl}-
piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole, (43)
3-ethyl-7-fluoro-1-[5-(1-{[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]methyl}-
piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole, (44)
1-[4-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piper-
idin-1-yl}methyl)piperidin-1-yl]-2-hydroxyethanone, (45)
1-[3-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piper-
idin-1-yl}methyl)azetidin-1-yl]-2-hydroxyethanone, (46)
1-{3-[(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5--
yl}piperidin-1-yl)methyl]azetidin-1-yl}-2-methoxyethanone, (47)
1-{3-[(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5--
yl}piperidin-1-yl)methyl]azetidin-1-yl}ethanone, (48) methyl
3-[(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-
piperidin-1-yl)methyl]azetidine-1-carboxylate, (49)
1-[3-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piper-
idin-1-yl}methyl)azetidin-1-yl]ethanone, (50)
1-{(2R)-2-[(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiaz-
ol-5-yl}piperidin-1-yl)methyl]pyrrolidin-1-yl}-2-hydroxyethanone,
(51)
1-(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}--
3'-methyl-1,4'-bipiperidin-1'-yl)-2-hydroxyethanone, (52)
1-(3-{[(3R)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadia-
zol-5-yl}methyl)pyrrolidin-1-yl]methyl}azetidin-1-yl)ethanone, (53)
1-(3-{[(3R)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadia-
zol-5-yl}methyl)pyrrolidin-1-yl]methyl}azetidin-1-yl)-2-hydroxyethanone,
(54)
1-[(3S)-3-{[(3R)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,-
2,4-oxadiazol-5-yl}methyl)pyrrolidin-1-yl]methyl}pyrrolidin-1-yl]ethanone,
(55)
1-[(3S)-3-{[(3R)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,-
2,4-oxadiazol-5-yl}methyl)pyrrolidin-1-yl]methyl}pyrrolidin-1-yl]-2-hydrox-
yethanone, (56)
1-[(3R)-3-{[(3R)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-o-
xadiazol-5-yl}methyl)pyrrolidin-1-yl]methyl}pyrrolidin-1-yl]-2-hydroxyetha-
none, (57)
1-[(2S)-2-{[(3S)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-y-
l]-1,2,4-oxadiazol-5-yl}methyl)pyrrolidin-1-yl]methyl}pyrrolidin-1-yl]-2-h-
ydroxyethanone, (58)
1-[(2R)-2-{[(3S)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-o-
xadiazol-5-yl}methyl)pyrrolidin-1-yl]methyl}pyrrolidin-1-yl]-2-hydroxyetha-
none, (59)
1-[(3S)-3-{[(3S)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-y-
l]-1,2,4-oxadiazol-5-yl}methyl)pyrrolidin-1-yl]methyl}pyrrolidin-1-yl]-2-h-
ydroxyethanone, (60)
1-[(3R)-3-{[(3S)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-o-
xadiazol-5-yl}methyl)pyrrolidin-1-yl]methyl}pyrrolidin-1-yl]-2-hydroxyetha-
none, (61)
1-{4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl-
]-4'-methyl-1,4'-bipiperidin-1'-yl}-2-hydroxyethanon, (62)
1-{4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-4'-methy-
l-1,4'-bipiperidin-1'-yl}-2-methoxyethanone, (63)
(2S)-1-{4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-4'--
methyl-1,4'-bipiperidin-1'-yl}-2-hydroxypropan-1-one, (64)
1-[(3S)-3-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-
piperidin-1-yl}methyl)pyrrolidin-1-yl]-2-hydroxyethanone, (65)
1-[(2S)-2-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-
piperidin-1-yl}methyl)pyrrolidin-1-yl]-2-hydroxyethanone, (66)
1-{4-[(3S)-3-{[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-
methyl}pyrrolidin-1-yl]piperidin-1-yl}ethanone, (67)
1-{4-[(3R)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiaz-
ol-5-yl}methyl)pyrrolidin-1-yl]piperidin-1-yl}-2-methoxyethanone,
(68)
1-(3-{[(3R)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadia-
zol-5-yl}methyl)pyrrolidin-1-yl]methyl}azetidin-1-yl)-2-methoxyethanone,
(69)
1-[(3S)-3-{[(3R)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,-
2,4-oxadiazol-5-yl}methyl)pyrrolidin-1-yl]methyl}pyrrolidin-1-yl]-2-methox-
yethanone, (70)
1-[(3R)-3-{[(3R)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-o-
xadiazol-5-yl}methyl)pyrrolidin-1-yl]methyl}pyrrolidin-1-yl]-2-methoxyetha-
none, (71)
1-{4-[(3S)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2-
,4-oxadiazol-5-yl}methyl)pyrrolidin-1-yl]piperidin-1-yl}-2-methoxyethanone-
, (72)
1-(3-{[(3S)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4--
oxadiazol-5-yl}methyl)pyrrolidin-1-yl]methyl}azetidin-1-yl)-2-methoxyethan-
one, (73)
1-[(3S)-3-{[(3S)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl-
]-1,2,4-oxadiazol-5-yl}methyl)pyrrolidin-1-yl]methyl}pyrrolidin-1-yl]-2-me-
thoxyethanone, and (74)
1-(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}--
3'-methyl-1,4'-bipiperidin-1'-yl)ethanone.
16. A pharmaceutical composition comprising the compound of claim 1
or a pharmaceutically acceptable salt thereof.
17. A serotonin-4 receptor agonist comprising the compound of claim
1 or a pharmaceutically acceptable salt thereof as an active
ingredient.
18. A medicament for treating Alzheimer-type dementia comprising
the compound of claim 1 or a pharmaceutically acceptable salt
thereof as an active ingredient.
19. A method for treating a disease associated with serotonin-4
receptor comprising administering a therapeutically effective
amount of the compound of claim 1 or a pharmaceutically acceptable
salt thereof to a patient in need thereof.
20. A method for treating Alzheimer-type dementia comprising
administering a therapeutically effective amount of the compound of
claim 1 or a pharmaceutically acceptable salt thereof to a patient
in need thereof.
Description
TECHNICAL FIELD
[0001] The present invention relates to a novel indazole- or
pyrrolopyridine-derivative which has an agonistic action or a
partial agonistic action against serotonin-4 receptor (hereinafter,
optionally referred to as 5-HT.sub.4 receptor), and a
pharmaceutical composition comprising the same.
BACKGROUND ART
[0002] 5-HT.sub.4 receptor which is a subtype of serotonin receptor
has been found in an action mechanism study of metoclopramide [i.e.
4-amino-5-chloro-N-(2-diethylamino-ethyl)-2-methoxybenzamide] which
is an enterokinesis-promoting agent or a digestive tract
function-improving agent in widespread clinical use (see,
Non-patent Reference 1). It has been known that 5-HT.sub.4 receptor
agonists promote enterokinesis in the peripheral part, and for
example, mosapride, cisapride and tegaserod have already been
marketed (provided that the sale of cisapride was stopped after
marketing). On the other hand, it has been reported that in the
central nerve system, 5-HT.sub.4 receptor agonists are effective in
improving cognitive function by enhancing the acetylcholine
release, and in increasing soluble APP .alpha. via the activation
of .alpha. secretase to lower the amount of beta-amyloid protein
(A.beta.) relatively (see, Non-patent Reference 2). PRX-03140 which
acts as a partial agonist to 5-HT.sub.4 receptor has been reported
to be efficacious for improving cognitive function and lowering
A.beta. in an animal experiment using rats (see, Non-patent
Reference 1). Furthermore, it has been reported that PRX-03140
shows the effect for improving cognitive function in a phase II
clinical trial with AD patients (see, Non-patent Reference 2).
Thus, 5-HT.sub.4 receptor agonists are expected to be a medicament
having a novel mechanism for treating various dementia caused by
Alzheimer-type dementia (AD) and neurodegenerative diseases.
Meanwhile, a super-aging society is coming in the near future, and
the number of patients suffering from Alzheimer-type dementia (AD)
is increasing rapidly. Hence, it has been strongly desired to
develop an efficacious medicament for treating Alzheimer-type
dementia.
[0003] It has also been known that an amide derivative having an
indazole is useful as an enterokinesis-promoting agent or a
digestive tract function-improving agent (see, Patent References 1
and 2).
[0004] However, there are no reports on an indazole or
pyrrolopyridine compound wherein the nitrogen atom at 1-position of
the indazole or pyrrolopyridine ring binds to an oxadiazole ring
and the like.
PRIOR ART DOCUMENT
Patent Reference
[0005] Patent REFERENCE 1: US 2005/197335 A1 [0006] Patent
Reference 2: US 2006/135764 A1
Non-Patent Reference
[0006] [0007] Non-patent Reference 1: 37th SFN Meeting (2007),
presentation abstract (poster presentation number 745.10/CCC12)
[0008] Non-patent Reference 2: International Conference on
Alzheimer's Disease (ICAD) 2008, presentation abstract, poster
presentation number HT-01-07
DISCLOSURE OF INVENTION
Problems to Be Solved by Invention
[0009] The problem to be solved by the present invention is to
provide a serotonin-4 receptor agonist useful as a medicament for
treating Alzheimer-type dementia and other similar diseases.
Means of Solving Problems
[0010] The present inventors have extensively studied the problem
and have found that a group of compounds comprising an
aromatic-ring moiety of indazole or pyrrolopyridine and a
bioisosteric structure of amide bond as a linker moiety to bind the
aromatic-ring moiety and an amine side chain (typically, oxadiazole
ring) shows an excellent agonistic activity against 5-HT.sub.4
receptors, and thus useful as a medicament for treating
Alzheimer-type dementia and similar diseases. Based upon the new
findings, the present invention has been completed. The present
invention can provide indazole derivatives and pyrrolopyridine
derivatives of the following Formula (1) (hereinafter, optionally
referred to as "the present compound").
Term 1
[0011] A compound of Formula (1):
##STR00001##
or a pharmaceutically acceptable salt thereof wherein A is the
following Formula (A-1), Formula (A-2), Formula (A-3), or Formula
(A-4):
##STR00002##
wherein l is an integer of 0 to 4, m is an integer of 0 to 2, n is
an integer of 0 to 2, o and p are independently an integer of 0 or
1, q is an integer of 0 to 5, (A-1) to (A-4) may be independently
and optionally substituted with one or more substituents
independently-selected from the group consisting of C.sub.1-6 alkyl
group, C.sub.2-6 alkenyl group, C.sub.2-6 alkynyl group, hydroxy
group, C.sub.1-6 alkoxy group, and halogen atom at each
substitutable position thereof, B is the following Formula (B-1),
Formula (B-2), or Formula (B-3):
##STR00003##
wherein (B-2) and (B-3) may optionally include an unsaturated
bond(s) at an acceptable position(s) of the ring, R.sup.8, R.sup.9
and D are independently a group selected from the group consisting
of the following (1) and (2): (1) hydrogen atom, an
optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.3-6 alkenyl group, an
optionally-substituted C.sub.3-6 alkynyl group, an
optionally-substituted C.sub.3-6 monocyclic, C.sub.7-70 bicyclic or
C.sub.7-12 tricyclic cycloalkyl group, and an
optionally-substituted C.sub.5-6 monocyclic or C.sub.7-10 bicyclic
cycloalkenyl group
[0012] wherein the C.sub.1-6 alkyl group, C.sub.3-6 alkenyl group,
C.sub.3-6 alkynyl group, C.sub.3-6 monocyclic, C.sub.7-10 bicyclic
or C.sub.7-12 tricyclic cycloalkyl group, and C.sub.5-6 monocyclic
or C.sub.7-70 bicyclic cycloalkenyl group may be independently and
optionally substituted with one or more substituents
independently-selected from the group consisting of C.sub.1-4 alkyl
group, hydroxy group, C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl
group, C.sub.1-4 haloalkoxy group, cyano group, oxo group, aryl
group, heteroaryl group, aryloxy group, C.sub.2-6 alkanoyl group,
phenacyl group, and halogen atom at each substitutable position
thereof;
(2) --(CH.sub.2).sub.u--R.sup.12
[0013] wherein u is an integer of 0 to 4 provided that when u is an
integer of 1 to 4, the alkylene chain may be optionally substituted
with one or more substituents independently-selected from the group
consisting of C.sub.1-6 alkyl group, C.sub.2-6 alkenyl group,
C.sub.2-6 alkynyl group, hydroxy group, C.sub.1-6 alkoxy group, oxo
group, and halogen atom,
R.sup.12 is the following Formula (R.sup.12-1), Formula
(R.sup.12-2), Formula (R.sup.12-3), Formula (R.sup.12-4), Formula
(R.sup.12-5), Formula (R.sup.12-6) Formula (R.sup.12-7), or Formula
(R.sup.12-8):
##STR00004##
wherein R.sup.13 is a group selected from the group consisting of
the following (1) to (5): (1) hydrogen atom and formyl group; (2)
an optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.3-6 alkenyl group, an
optionally-substituted C.sub.3-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, and an
optionally-substituted C.sub.5-8 cycloalkenyl group
[0014] wherein the C.sub.1-6 alkyl group, C.sub.3-6 alkenyl group,
C.sub.3-6 alkynyl group, C.sub.3-8 cycloalkyl group, and C.sub.5-8
cycloalkenyl group may be independently and optionally substituted
with one or more substituents independently-selected from the group
consisting of C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4
alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy
group, cyano group, oxo group, and halogen atom at each
substitutable position thereof; [0015] (3) --COR.sup.16,
--CSR.sup.16, --SO.sub.2R.sup.16, --CO--COR.sup.16, --COOR.sup.16,
and --CO--COOR.sup.16
[0016] wherein R.sup.16 is an optionally-substituted C.sub.1-6
alkyl group, an optionally-substituted C.sub.3-6 alkenyl group, an
optionally-substituted C.sub.3-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted C.sub.5-8 cycloalkenyl group, an
optionally-substituted aryl group, an optionally-substituted
heteroaryl group, an optionally-substituted 5- to 9-membered
monocyclic or 7- to 10-membered bicyclic non-aromatic unsaturated
heterocyclic group (wherein the binding site is any one carbon atom
in the heterocyclic ring), or an optionally-substituted 4- to
9-membered monocyclic or 7- to 10-membered bicyclic saturated
heterocyclic group (wherein the binding site is any one carbon atom
in the heterocyclic ring),
[0017] wherein the C.sub.1-6 alkyl group, C.sub.3-6 alkenyl group,
C.sub.3-6 alkynyl group, C.sub.3-6 cycloalkyl group, C.sub.6-6
cycloalkenyl group, 5- to 9-membered monocyclic or 7- to
10-membered bicyclic non-aromatic unsaturated heterocyclic group,
and 4- to 9-membered monocyclic or 7- to 10-membered bicyclic
saturated heterocyclic group may be independently and optionally
substituted with one or more substituents independently-selected
from the group consisting of C.sub.1-4 alkyl group, hydroxy group,
C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4
haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl
group, and halogen atom at each substitutable position thereof; and
the aryl group and heteroaryl group may be independently and
optionally substituted with one or more substituents
independently-selected from the group consisting of halogen atom,
hydroxy group, C.sub.1-4 alkyl group, C.sub.1-4 alkoxy group,
C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy group, cyano group,
nitro group, C.sub.2-6 alkanoyl group, and an
optionally-substituted amino group at each substitutable position
thereof; [0018] (4) --CONR.sup.17--OR.sup.18
[0019] wherein R.sup.17 and R.sup.18 are independently hydrogen
atom, C.sub.1-6 alkyl group, C.sub.3-6 alkenyl group or C.sub.3-6
alkynyl group;
(5) --CONR.sup.18R.sup.20, CSNR.sup.19R.sup.20 and
--SO.sub.2NR.sup.19R.sup.20
[0020] wherein R.sup.10 and R.sup.20 are independently hydrogen
atom or any group defined in the said R.sup.16, or
[0021] R.sup.19 and R.sup.20 may be taken together with the
adjacent nitrogen atom to form a saturated or unsaturated 4- to
8-membered monocyclic nitrogen-containing heterocyclic group
comprising additional 0 to 2 heteroatoms independently-selected
from the group consisting of 1 to 2 nitrogen atoms, 1 oxygen atom
and 1 sulfur atom wherein the heterocyclic group may be optionally
substituted with one or more substituents independently-selected
from the group consisting of C.sub.1-4 alkyl group, hydroxy group,
C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4
haloalkoxy group, cyano group, oxo group, and halogen atom at each
substitutable position thereof,
R.sup.14 and R.sup.15 are independently hydrogen atom, an
optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.3-6 alkenyl group, an
optionally-substituted C.sub.3-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted C.sub.5-8 cycloalkenyl group, an
optionally-substituted aryl group, an optionally-substituted
heteroaryl group, an optionally-substituted 5- to 9-membered
monocyclic or 7- to 10-membered bicyclic non-aromatic unsaturated
heterocyclic group (which is attached to the adjacent nitrogen atom
via any one carbon atom in the heterocyclic group), an
optionally-substituted 4- to 9-membered monocyclic or 7- to
10-membered bicyclic saturated heterocyclic group (which is
attached to the adjacent nitrogen atom via any one carbon atom in
the heterocyclic group), C.sub.2-6 alkanoyl group, C.sub.1-6
alkoxycarbonyl group, carbamoyl group, sulfamoyl group, or
C.sub.1-6 alkylsulfonyl group,
[0022] wherein the C.sub.1-6 alkyl group, C.sub.3-6 alkenyl group,
C.sub.3-6 alkynyl group, C.sub.3-8 cycloalkyl group, C.sub.5-8
cycloalkenyl group, 5- to 9-membered monocyclic or 7- to
10-membered bicyclic non-aromatic unsaturated heterocyclic group,
4- to 9-membered monocyclic or 7- to 10-membered bicyclic saturated
heterocyclic group, C.sub.2-6 alkanoyl group, C.sub.1-6
alkoxycarbonyl group, and C.sub.1-6 alkylsulfonyl group may be
independently and optionally substituted with one or more
substituents independently-selected from the group consisting of
C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy group, cyano
group, oxo group, aryl group, heteroaryl group, and halogen atom at
each substitutable position thereof; and the aryl group and
heteroaryl group may be independently and optionally substituted
with one or more substituents independently-selected from the group
consisting of halogen atom, hydroxy group, C.sub.1-4 alkyl group,
C.sub.1-4 alkoxy group, cyano group, nitro group, C.sub.2-6
alkanoyl group, and an optionally-substituted amino group at each
substitutable position thereof, or
R.sup.14 and R.sup.15 may be taken together with the adjacent
nitrogen atom to form a saturated or unsaturated 4- to 9-membered
monocyclic or 7- to 10-membered bicyclic nitrogen-containing
heterocyclic group comprising additional 0 to 2 heteroatoms
independently-selected from the group consisting of 1 to 2 nitrogen
atoms, 1 oxygen atom and 1 sulfur atom wherein the heterocyclic
group may be optionally substituted with one or more substituents
independently-selected from the group consisting of C.sub.1-4 alkyl
group, hydroxy group, C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl
group, C.sub.1-4 haloalkoxy group, cyano group, oxo group, and
halogen atom at each substitutable position thereof, (R.sup.12-1)
to (R.sup.12-4) may optionally include an unsaturated bond(s) at an
acceptable position(s) of the ring, R.sup.8' and R.sup.9' are
independently hydrogen atom, an optionally-substituted C.sub.1-8
alkyl group, an optionally-substituted C.sub.3-6 alkenyl group, an
optionally-substituted C.sub.3-8 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted C.sub.5-8 cycloalkenyl group, an
optionally-substituted aryl group, an optionally-substituted
heteroaryl group, an optionally-substituted 5- to 9-membered
monocyclic or 7- to 10-membered bicyclic non-aromatic unsaturated
heterocyclic group (which is attached to the adjacent nitrogen atom
via any one carbon atom in the heterocyclic group), or an
optionally-substituted 4- to 9-membered monocyclic or 7- to
10-membered bicyclic saturated heterocyclic group (which is
attached to the adjacent nitrogen atom via any one carbon atom in
the heterocyclic group),
[0023] wherein the C.sub.1-6 alkyl group, C.sub.3-6 alkenyl group,
C.sub.3-6 alkynyl group, C.sub.3-8 cycloalkyl group, C.sub.5-8
cycloalkenyl group, 5- to 9-membered monocyclic or 7- to
10-membered bicyclic non-aromatic unsaturated heterocyclic group,
and 4- to 9-membered monocyclic or 7- to 10-membered bicyclic
saturated heterocyclic group may be independently and optionally
substituted with one or more substituents independently-selected
from the group consisting of C.sub.1-4 alkyl group, hydroxy group,
C.sub.1-4 alkoxy group, C.sub.1-4 haloalkoxy group, cyano group,
oxo group, aryl group, heteroaryl group, aryloxy group, C.sub.2-6
alkanoyl group, phenacyl group, and halogen atom at each
substitutable position thereof; and the aryl group and heteroaryl
group may be independently and optionally substituted with one or
more substituents independently-selected from the group consisting
of halogen atom, hydroxy group, C.sub.1-4 alkyl group, C.sub.1-4
alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy
group, cyano group, nitro group, C.sub.2-6 alkanoyl group, and an
optionally-substituted amino group at each substitutable position
thereof, or a pair of R.sup.8 and R.sup.9, and a pair of R.sup.8'
and R.sup.9' may be independently taken together with the adjacent
nitrogen atom to form a saturated or unsaturated 4- to 9-membered
monocyclic or 7- to 10-membered bicyclic nitrogen-containing
heterocyclic group comprising additional 0 to 2 heteroatoms
independently-selected from the group consisting of 1 to 2 nitrogen
atoms, 1 oxygen atom and 1 sulfur atom wherein the
nitrogen-containing heterocyclic group may be optionally
substituted with one or more substituents independently-selected
from the group consisting of C.sub.1-4 alkyl group, hydroxy group,
C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4
haloalkoxy group, cyano group, oxo group, and halogen atom at each
substitutable position thereof,
R.sup.10, R.sup.10', R.sup.11 and R.sup.11' are independently
hydrogen atom, halogen atom, hydroxy group, an
optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.2-6 alkenyl group, an
optionally-substituted C.sub.2-6 alkynyl group, an
optionally-substituted C.sub.1-6 alkoxy group, cyano group, or an
oxo group,
[0024] wherein the C.sub.1-6 alkyl group, C.sub.2-6 alkenyl group,
C.sub.2-6 alkynyl group, and C.sub.1-6 alkoxy group may be
independently and optionally substituted with one or more
substituents independently-selected from the group consisting of
C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy group,
C.sub.1-4 haloalkoxy group, cyano group, oxo group, aryl group,
heteroaryl group, aryloxy group, C.sub.2-6 alkanoyl group, phenacyl
group, and halogen atom at each substitutable position thereof,
or
a pair of R.sup.10 and R.sup.11, and a pair of R.sup.10' and
R.sup.11' may be independently taken together to form an
optionally-substituted saturated or unsaturated 3- to 8-membered
ring that may comprise 1 oxygen atom, which may be a bicyclic or a
spiro compound with the ring to which the pair of R.sup.10 and
R.sup.11, or R.sup.10' and R.sup.11' is attached,
[0025] wherein the saturated or unsaturated 3- to 8-membered ring
may be optionally substituted with one or more substituents
independently-selected from the group consisting of C.sub.1-4 alkyl
group, hydroxy group, C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl
group, C.sub.1-4 haloalkoxy group, cyano group, oxo group, aryl
group, heteroaryl group, aryloxy group, C.sub.2-6 alkanoyl group,
phenacyl group, and halogen atom at each substitutable position
thereof,
r and r' are independently an integer of 0 to 3, s and s' are
independently an integer of 0 to 3, t and t' are independently 1 or
2, v is an integer of 0 to 2, provided that not both r and s are 0,
V is nitrogen atom or C--R.sup.1 wherein R.sup.1 is hydrogen atom,
halogen atom, an optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.2-6 alkenyl group, an
optionally-substituted C.sub.2-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted C.sub.5-8 cycloalkenyl group, an
optionally-substituted aryl group, or an optionally-substituted
heteroaryl group,
[0026] wherein the C.sub.1-6 alkyl group, C.sub.2-6 alkenyl group,
C.sub.2-6 alkynyl group, C.sub.3-8 cycloalkyl group, and C.sub.5-8
cycloalkenyl group may be independently and optionally substituted
with one or more substituents independently-selected from the group
consisting of C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4
alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy
group, cyano group, oxo group, aryl group, heteroaryl group,
aryloxy group, C.sub.2-6 alkanoyl group, phenacyl group, and
halogen atom at each substitutable position thereof; and the aryl
group and heteroaryl group may be independently and optionally
substituted with one or more substituents independently-selected
from the group consisting of halogen atom, hydroxy group, C.sub.1-4
alkyl group, C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl group,
C.sub.1-4 haloalkoxy group, cyano group, nitro group, C.sub.2-6
alkanoyl group, and an optionally-substituted amino group at each
substitutable position thereof,
W is nitrogen atom or C--R.sup.2 wherein R.sup.2 is hydrogen atom,
halogen atom, hydroxy group, an optionally-substituted C.sub.1-6
alkyl group, an optionally-substituted C.sub.2-6 alkenyl group, an
optionally-substituted C.sub.2-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted C.sub.5-8 cycloalkenyl group, an
optionally-substituted C.sub.1-6 alkoxy group, an
optionally-substituted C.sub.1-4 haloalkyl group, an
optionally-substituted C.sub.1-4 haloalkoxy group, cyano group,
nitro group, an optionally-substituted aryl group, an
optionally-substituted heteroaryl group, or an
optionally-substituted amino group,
[0027] wherein the C.sub.1-6 alkyl group, C.sub.2-6 alkenyl group,
C.sub.2-6 alkynyl group, C.sub.3-8 cycloalkyl group, C.sub.5-8
cycloalkenyl group, C.sub.1-6 alkoxy group, C.sub.1-4 haloalkyl
group, and C.sub.1-4 haloalkoxy group may be independently and
optionally substituted with one or more substituents
independently-selected from the group consisting of C.sub.1-4 alkyl
group, hydroxy group, C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl
group, C.sub.1-4 haloalkoxy group, cyano group, oxo group, aryl
group, heteroaryl group, aryloxy group, C.sub.2-6 alkanoyl group,
phenacyl group, and halogen atom at each substitutable position
thereof; and the aryl group and heteroaryl group may be
independently and optionally substituted with one or more
substituents independently-selected from the group consisting of
halogen atom, hydroxy group, C.sub.1-4 alkyl group, C.sub.1-4
alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy
group, cyano group, nitro group, C.sub.2-6 alkanoyl group, and an
optionally-substituted amino group at each substitutable position
thereof,
[0028] provided that when V is C--R.sup.1, W is nitrogen atom, and
when V is nitrogen atom, W is C--R.sup.2,
U is carbon atom or nitrogen atom, X, Y and Z are independently
selected from the group consisting of oxygen atom, nitrogen atom,
sulfur atom and carbon atom, provided that at least one of X, Y and
Z is oxygen atom, sulfur atom, or nitrogen atom, R.sup.3 is
hydrogen atom, halogen atom, an optionally-substituted C.sub.1-6
alkyl group, an optionally-substituted C.sub.2-6 alkenyl group, an
optionally-substituted C.sub.2-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted C.sub.5-8 cycloalkenyl group, an
optionally-substituted C.sub.1-6 alkoxy group, an
optionally-substituted C.sub.1-4 haloalkyl group, an
optionally-substituted C.sub.1-4 haloalkoxy group, cyano group,
nitro group, an optionally-substituted aryl group, an
optionally-substituted heteroaryl group, an optionally-substituted
5- to 9-membered monocyclic or 7- to 10-membered bicyclic
non-aromatic unsaturated heterocyclic group, or an
optionally-substituted 4- to 9-membered monocyclic or 7- to
10-membered bicyclic saturated heterocyclic group,
[0029] wherein the C.sub.1-6 alkyl group, C.sub.2-6 alkenyl group,
C.sub.2-6 alkynyl group, C.sub.3-6 cycloalkyl group, C.sub.5-6
cycloalkenyl group, alkoxy group, C.sub.1-4 haloalkyl group,
C.sub.1-4 haloalkoxy group, 5- to 9-membered monocyclic or 7- to
10-membered bicyclic non-aromatic unsaturated heterocyclic group,
and 4- to 9-membered monocyclic or 7- to 10-membered bicyclic
saturated heterocyclic group may be independently and optionally
substituted with one or more substituents independently-selected
from the group consisting of C.sub.1-4 alkyl group, hydroxy group,
C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4
haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl
group, aryloxy group, C.sub.2-6 alkanoyl group, phenacyl group, and
halogen atom at each substitutable position thereof; and the aryl
group and heteroaryl group may be independently and optionally
substituted with one or more substituents independently-selected
from the group consisting of halogen atom, hydroxy group, C.sub.1-4
alkyl group, C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl group,
C.sub.1-4 haloalkoxy group, cyano group, nitro group, C.sub.2-6
alkanoyl group, and an optionally-substituted amino group at each
substitutable position thereof,
R.sup.4 is hydrogen atom, halogen atom, hydroxy group, an
optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.2-6 alkenyl group, an
optionally-substituted C.sub.2-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted C.sub.5-8 cycloalkenyl group, an
optionally-substituted C.sub.1-6 alkoxy group, an
optionally-substituted C.sub.1-4 haloalkyl group, an
optionally-substituted C.sub.1-4 haloalkoxy group, cyano group,
nitro group, an optionally-substituted aryl group, an
optionally-substituted heteroaryl group, or an
optionally-substituted amino group,
[0030] wherein the C.sub.1-6 alkyl group, C.sub.2-6 alkenyl group,
C.sub.2-6 alkynyl group, C.sub.3-8 cycloalkyl group, C.sub.5-8
cycloalkenyl group, C.sub.1-6 alkoxy group, C.sub.1-4 haloalkyl
group, and C.sub.1-4 haloalkoxy group may be independently and
optionally substituted with one or more substituents
independently-selected from the group consisting of C.sub.1-4 alkyl
group, hydroxy group, C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl
group, C.sub.1-4 haloalkoxy group, cyano group, oxo group, aryl
group, heteroaryl group, aryloxy group, C.sub.2-6 alkanoyl group,
phenacyl group, and halogen atom at each substitutable position
thereof; and the aryl group and heteroaryl group may be
independently and optionally substituted with one or more
substituents independently-selected from the group consisting of
halogen atom, hydroxy group, C.sub.1-4 alkyl group, C.sub.1-4
alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy
group, cyano group, nitro group, C.sub.2-6 alkanoyl group, and an
optionally-substituted amino group at each substitutable position
thereof, or
R.sup.3 and R.sup.4 may be taken together to form a saturated or
unsaturated 6- to 9-membered ring optionally comprising 1 oxygen
atom wherein the ring may be optionally substituted with one or
more substituents independently-selected from the group consisting
of C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy group,
C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy group, cyano group,
oxo group, and halogen atom at each substitutable position thereof,
and R.sup.5 and R.sup.6 are independently hydrogen atom, halogen
atom, hydroxy group, an optionally-substituted C.sub.1-6 alkyl
group, an optionally-substituted C.sub.2-6 alkenyl group, an
optionally-substituted C.sub.2-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted C.sub.8-8 cycloalkenyl group, an
optionally-substituted C.sub.1-6 alkoxy group, an
optionally-substituted C.sub.1-4 haloalkyl group, an
optionally-substituted C.sub.1-4 haloalkoxy group, cyano group,
nitro group, an optionally-substituted aryl group, an
optionally-substituted heteroaryl group, or an
optionally-substituted amino group,
[0031] wherein the C.sub.1-6 alkyl group, C.sub.2-6 alkenyl group,
C.sub.2-6 alkynyl group, C.sub.3-8 cycloalkyl group, C.sub.8-8
cycloalkenyl group, C.sub.1-6 alkoxy group, C.sub.1-4 haloalkyl
group, and C.sub.1-4 haloalkoxy group may be independently and
optionally substituted with one or more substituents
independently-selected from the group consisting of C.sub.1-4 alkyl
group, hydroxy group, C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl
group, C.sub.1-4 haloalkoxy group, cyano group, oxo group, aryl
group, heteroaryl group, aryloxy group, C.sub.2-6 alkanoyl group,
phenacyl group, and halogen atom at each substitutable position
thereof; and the aryl group and heteroaryl group may be
independently and optionally substituted with one or more
substituents independently-selected from the group consisting of
halogen atom, hydroxy group, C.sub.1-4 alkyl group, C.sub.1-4
alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy
group, cyano group, nitro group, C.sub.2-6 alkanoyl group, and an
optionally-substituted amino group at each substitutable position
thereof.
Term 2
[0032] A compound of Formula (1):
##STR00005##
or a pharmaceutically acceptable salt thereof wherein A is the
following Formula (A-1), Formula (A-2), Formula (A-3), or Formula
(A-4):
##STR00006##
wherein l is an integer of 0 to 4, m is an integer of 0 to 2, n is
an integer of 0 to 2, o and p are independently an integer of 0 or
1, q is an integer of 0 to 5, (A-1) to (A-4) may be independently
and optionally substituted with one or more substituents
independently-selected from the group consisting of C.sub.1-6 alkyl
group, C.sub.2-6 alkenyl group, C.sub.2-6 alkynyl group, hydroxy
group, C.sub.1-6 alkoxy group, oxo group and halogen atom at each
substitutable position thereof, B is the following Formula (B-1),
Formula (B-2), or Formula (B-3):
##STR00007##
wherein (B-2) and (B-3) may optionally include an unsaturated
bond(s) at an acceptable position(s) of the ring, and D is absent
when B is Formula (B-1), D is independently a group selected from
the group consisting of the following (1) and (2): (1) hydrogen
atom, an optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.3-6 alkenyl group, an
optionally-substituted C.sub.3-6 alkynyl group, an
optionally-substituted C.sub.3-8 monocyclic, C.sub.7-10 bicyclic or
C.sub.7-12 tricyclic cycloalkyl group, and an
optionally-substituted C.sub.5-8 monocyclic or C.sub.7-10 bicyclic
cycloalkenyl group
[0033] wherein the C.sub.1-6 alkyl group, C.sub.3-6 alkenyl group,
C.sub.3-6 alkynyl group, C.sub.3-8 monocyclic, C.sub.7-10 bicyclic
or C.sub.7-12 tricyclic cycloalkyl group, and C.sub.5-8 monocyclic
or C.sub.7-10 bicyclic cycloalkenyl group may be independently and
optionally substituted with one or more substituents
independently-selected from the group consisting of C.sub.1-4 alkyl
group, hydroxy group, C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl
group, C.sub.1-4 haloalkoxy group, cyano group, oxo group, aryl
group, heteroaryl group, aryloxy group, C.sub.2-6 alkanoyl group,
phenacyl group, and halogen atom at each substitutable position
thereof;
(2) --(CH.sub.2).sub.u--R.sup.12
[0034] wherein u is an integer of 0 to 4 provided that when u is an
integer of 1 to 4, the alkylene chain may be optionally substituted
with one or more substituents independently-selected from the group
consisting of C.sub.1-6 alkyl group, C.sub.2-6 alkenyl group,
C.sub.2-6 alkynyl group, hydroxy group, C.sub.1-6 alkoxy group, oxo
group, and halogen atom,
R.sup.12 is the following Formula (R.sup.12-1), Formula
(R.sup.12-2), Formula (R.sup.12-3), Formula (R.sup.12-4), Formula
(R.sup.12-5), Formula (R.sup.12-6), Formula (R.sup.12-7), or
Formula (R.sup.12-8):
##STR00008##
wherein R.sup.13 is a group selected from the group consisting of
the following (1) to (5): (1) hydrogen atom and formyl group; (2)
an optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.3-6 alkenyl group, an
optionally-substituted C.sub.3-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, and an
optionally-substituted C.sub.5-8 cycloalkenyl group
[0035] wherein the C.sub.1-6 alkyl group, C.sub.3-6 alkenyl group,
C.sub.3-6 alkynyl group, C.sub.3-8 cycloalkyl group, and C.sub.5-8
cycloalkenyl group may be independently and optionally substituted
with one or more substituents independently-selected from the group
consisting of C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4
alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy
group, cyano group, oxo group, and halogen atom at each
substitutable position thereof; [0036] (3) --COR.sup.16,
--CSR.sup.16, --SO.sub.2R.sup.16, --CO--COR.sup.16, COOR.sup.16,
and --CO--COOR.sup.16
[0037] wherein R.sup.16 is an optionally-substituted C.sub.1-6
alkyl group, an optionally-substituted C.sub.3-6 alkenyl group, an
optionally-substituted C.sub.3-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted C.sub.5-8 cycloalkenyl group, an
optionally-substituted aryl group, an optionally-substituted
heteroaryl group, an optionally-substituted 5- to 9-membered
monocyclic or 7- to 10-membered bicyclic non-aromatic unsaturated
heterocyclic group (wherein the binding site is any one carbon atom
in the heterocyclic ring), or an optionally-substituted 4- to
9-membered monocyclic or 7- to 10-membered bicyclic saturated
heterocyclic group (wherein the binding site is any one carbon atom
in the heterocyclic ring),
[0038] wherein the C.sub.1-6 alkyl group, C.sub.3-6 alkenyl group,
C.sub.3-6 alkynyl group, C.sub.3-8 cycloalkyl group, C.sub.5-8
cycloalkenyl group, 5- to 9-membered monocyclic or 7- to
10-membered bicyclic non-aromatic unsaturated heterocyclic group,
and 4- to 9-membered monocyclic or 7- to 10-membered bicyclic
saturated heterocyclic group may be independently and optionally
substituted with one or more substituents independently-selected
from the group consisting of C.sub.1-4 alkyl group, hydroxy group,
C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4
haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl
group, and halogen atom at each substitutable position thereof; and
the aryl group and heteroaryl group may be independently and
optionally substituted with one or more substituents
independently-selected from the group consisting of halogen atom,
hydroxy group, C.sub.1-4 alkyl group, C.sub.1-4 alkoxy group,
C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy group, cyano group,
nitro group, C.sub.2-6 alkanoyl group, and an
optionally-substituted amino group at each substitutable position
thereof;
(4) --CONR.sup.17--OR.sup.18
[0039] wherein R.sup.17 and R.sup.18 are independently hydrogen
atom, C.sub.1-6 alkyl group, C.sub.3-6 alkenyl group or C.sub.3-6
alkynyl group;
(5) --CONR.sup.19R.sup.20CSNR.sup.19R.sup.20 and
--SO.sub.2NR.sup.19R.sup.20
[0040] wherein R.sup.18 and R.sup.20 are independently hydrogen
atom or any group defined in the said R.sup.18, or
[0041] R.sup.18 and R.sup.20 may be taken together with the
adjacent nitrogen atom to form a saturated or unsaturated 4- to
8-membered monocyclic nitrogen-containing heterocyclic group
comprising additional 0 to 2 heteroatoms independently-selected
from the group consisting of 1 to 2 nitrogen atoms, 1 oxygen atom
and 1 sulfur atom wherein the heterocyclic group may be optionally
substituted with one or more substituents independently-selected
from the group consisting of C.sub.1-4 alkyl group, hydroxy group,
C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4
haloalkoxy group, cyano group, oxo group, and halogen atom at each
substitutable position thereof,
R.sup.14 and R.sup.15 are independently hydrogen atom, an
optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.3-6 alkenyl group, an
optionally-substituted C.sub.3-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted C.sub.5-8 cycloalkenyl group, an
optionally-substituted aryl group, an optionally-substituted
heteroaryl group, an optionally-substituted 5- to 9-membered
monocyclic or 7- to 10-membered bicyclic non-aromatic unsaturated
heterocyclic group (which is attached to the adjacent nitrogen atom
via any one carbon atom in the heterocyclic group), an
optionally-substituted 4- to 9-membered monocyclic or 7- to
10-membered bicyclic saturated heterocyclic group (which is
attached to the adjacent nitrogen atom via any one carbon atom in
the heterocyclic group), C.sub.2-6 alkanoyl group, C.sub.1-6
alkoxycarbonyl group, carbamoyl group, sulfamoyl group, or
C.sub.1-6 alkylsulfonyl group,
[0042] wherein the C.sub.1-6 alkyl group, C.sub.3-6 alkenyl group,
C.sub.3-6 alkynyl group, C.sub.3-8 cycloalkyl group, C.sub.5-8
cycloalkenyl group, 5- to 9-membered monocyclic or 7- to
10-membered bicyclic non-aromatic unsaturated heterocyclic group,
4- to 9-membered monocyclic or 7- to 10-membered bicyclic saturated
heterocyclic group, C.sub.2-6 alkanoyl group, C.sub.1-6
alkoxycarbonyl group, and C.sub.1-6 alkylsulfonyl group may be
independently and optionally substituted with one or more
substituents independently-selected from the group consisting of
C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy group, cyano
group, oxo group, aryl group, heteroaryl group, and halogen atom at
each substitutable position thereof; and the aryl group and
heteroaryl group may be independently and optionally substituted
with one or more substituents independently-selected from the group
consisting of halogen atom, hydroxy group, C.sub.1-4 alkyl group,
C.sub.1-4 alkoxy group, cyano group, nitro group, C.sub.2-6
alkanoyl group, and an optionally-substituted amino group at each
substitutable position thereof, or
R.sup.14 and R.sup.15 may be taken together with the adjacent
nitrogen atom to form a saturated or unsaturated 4- to 9-membered
monocyclic or 7- to 10-membered bicyclic nitrogen-containing
heterocyclic group comprising additional 0 to 2 heteroatoms
independently-selected from the group consisting of 1 to 2 nitrogen
atoms, 1 oxygen atom and 1 sulfur atom wherein the heterocyclic
group may be optionally substituted with one or more substituents
independently-selected from the group consisting of C.sub.1-4 alkyl
group, hydroxy group, C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl
group, C.sub.1-4 haloalkoxy group, cyano group, oxo group, and
halogen atom at each substitutable position thereof, (R.sup.12-1)
to (R.sup.12-4) may optionally include an unsaturated bond(s) at an
acceptable position(s) of the ring, R.sup.8, R.sup.8', R.sup.9 and
R.sup.9' are independently hydrogen atom, an optionally-substituted
C.sub.1-6 alkyl group, an optionally-substituted C.sub.3-6 alkenyl
group, an optionally-substituted C.sub.3-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted C.sub.5-8 cycloalkenyl group, an
optionally-substituted aryl group, an optionally-substituted
heteroaryl group, an optionally-substituted 5- to 9-membered
monocyclic or 7- to 10-membered bicyclic non-aromatic unsaturated
heterocyclic group (which is attached to the adjacent nitrogen atom
via any one carbon atom in the heterocyclic group), or an
optionally-substituted 4- to 9-membered monocyclic or 7- to
10-membered bicyclic saturated heterocyclic group (which is
attached to the adjacent nitrogen atom via any one carbon atom in
the heterocyclic group),
[0043] wherein the C.sub.1-6 alkyl group, C.sub.3-6 alkenyl group,
C.sub.3-6 alkynyl group, C.sub.3-8 cycloalkyl group, C.sub.5-8
cycloalkenyl group, 5- to 9-membered monocyclic or 7- to
10-membered bicyclic non-aromatic unsaturated heterocyclic group,
and 4- to 9-membered monocyclic or 7- to 10-membered bicyclic
saturated heterocyclic group may be independently and optionally
substituted with one or more substituents independently-selected
from the group consisting of C.sub.1-4 alkyl group, hydroxy group,
C.sub.1-4 alkoxy group, C.sub.1-4 haloalkoxy group, cyano group,
oxo group, aryl group, heteroaryl group, aryloxy group, C.sub.2-6
alkanoyl group, phenacyl group, and halogen atom at each
substitutable position thereof; and the aryl group and heteroaryl
group may be independently and optionally substituted with one or
more substituents independently-selected from the group consisting
of halogen atom, hydroxy group, C.sub.1-4 alkyl group, C.sub.1-4
alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy
group, cyano group, nitro group, C.sub.2-6 alkanoyl group, and an
optionally-substituted amino group at each substitutable position
thereof, or a pair of R.sup.8 and R.sup.9, and a pair of R.sup.8'
and R.sup.9' may be independently taken together with the adjacent
nitrogen atom to form a saturated or unsaturated 4- to 9-membered
monocyclic or 7- to 10-membered bicyclic nitrogen-containing
heterocyclic group comprising additional 0 to 2 heteroatoms
independently-selected from the group consisting of 1 to 2 nitrogen
atoms, 1 oxygen atom and 1 sulfur atom wherein the
nitrogen-containing heterocyclic group may be optionally
substituted with one or more substituents independently-selected
from the group consisting of C.sub.1-4 alkyl group, hydroxy group,
C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4
haloalkoxy group, cyano group, oxo group, and halogen atom at each
substitutable position thereof,
R.sup.10, R.sup.10', R.sup.11 and R.sup.11' are independently
hydrogen atom, halogen atom, hydroxy group, an
optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.2-6 alkenyl group, an
optionally-substituted C.sub.2-6 alkynyl group, an
optionally-substituted C.sub.1-6 alkoxy group, cyano group, or an
oxo group,
[0044] wherein the C.sub.1-6 alkyl group, C.sub.2-6 alkenyl group,
C.sub.2-6 alkynyl group, and C.sub.1-6 alkoxy group may be
independently and optionally substituted with one or more
substituents independently-selected from the group consisting of
C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy group,
C.sub.1-4 haloalkoxy group, cyano group, oxo group, aryl group,
heteroaryl group, aryloxy group, C.sub.2-6 alkanoyl group, phenacyl
group, and halogen atom at each substitutable position thereof,
or
a pair of R.sup.10 and R.sup.11, and a pair of R.sup.10' and
R.sup.11' may be independently taken together to form an
optionally-substituted saturated or unsaturated 3- to 8-membered
ring that may comprise 1 oxygen atom, which may be a bicyclic or a
spiro compound with the ring to which the pair of R.sup.10 and
R.sup.11 is attached,
[0045] wherein the saturated or unsaturated 3- to 8-membered ring
may be optionally substituted with one or more substituents
independently-selected from the group consisting of C.sub.1-4 alkyl
group, hydroxy group, C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl
group, C.sub.1-4 haloalkoxy group, cyano group, oxo group, aryl
group, heteroaryl group, aryloxy group, C.sub.2-6 alkanoyl group,
phenacyl group, and halogen atom at each substitutable position
thereof,
r and r' are independently an integer of 0 to 3, s and s' are
independently an integer of 0 to 3, t and t' are independently 1 or
2, v is an integer of 0 to 2, provided that not both r and s are 0,
V is nitrogen atom or C--R.sup.1 wherein R.sup.1 is hydrogen atom,
halogen atom, an optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.2-6 alkenyl group, an
optionally-substituted C.sub.2-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted C.sub.5-8 cycloalkenyl group, an
optionally-substituted aryl group, or an optionally-substituted
heteroaryl group,
[0046] wherein the C.sub.1-6 alkyl group, C.sub.2-6 alkenyl group,
C.sub.2-6 alkynyl group, C.sub.3-8 cycloalkyl group, and C.sub.5-8
cycloalkenyl group may be independently and optionally substituted
with one or more substituents independently-selected from the group
consisting of C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4
alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy
group, cyano group, oxo group, aryl group, heteroaryl group,
aryloxy group, C.sub.2-6 alkanoyl group, phenacyl group, and
halogen atom at each substitutable position thereof; and the aryl
group and heteroaryl group may be independently and optionally
substituted with one or more substituents independently-selected
from the group consisting of halogen atom, hydroxy group, C.sub.1-4
alkyl group, C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl group,
C.sub.1-4 haloalkoxy group, cyano group, nitro group, C.sub.2-6
alkanoyl group, and an optionally-substituted amino group at each
substitutable position thereof,
W is nitrogen atom or C--R.sup.2 wherein R.sup.2 is hydrogen atom,
halogen atom, hydroxy group, an optionally-substituted C.sub.1-6
alkyl group, an optionally-substituted C.sub.2-6 alkenyl group, an
optionally-substituted C.sub.2-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted C.sub.5-8 cycloalkenyl group, an
optionally-substituted C.sub.1-6 alkoxy group, an
optionally-substituted C.sub.1-4 haloalkyl group, an
optionally-substituted C.sub.1-4 haloalkoxy group, cyano group,
nitro group, an optionally-substituted aryl group, an
optionally-substituted heteroaryl group, or an
optionally-substituted amino group,
[0047] wherein the C.sub.1-6 alkyl group, C.sub.2-6 alkenyl group,
C.sub.2-6 alkynyl group, C.sub.3-8 cycloalkyl group, C.sub.5-8
cycloalkenyl group, C.sub.1-6 alkoxy group, C.sub.1-4 haloalkyl
group, and C.sub.1-4 haloalkoxy group may be independently and
optionally substituted with one or more substituents
independently-selected from the group consisting of C.sub.1-4 alkyl
group, hydroxy group, C.sub.1-4 alkoxy group, haloalkyl group,
C.sub.1-4 haloalkoxy group, cyano group, oxo group, aryl group,
heteroaryl group, aryloxy group, C.sub.2-6 alkanoyl group, phenacyl
group, and halogen atom at each substitutable position thereof; and
the aryl group and heteroaryl group may be independently and
optionally substituted with one or more substituents
independently-selected from the group consisting of halogen atom,
hydroxy group, C.sub.1-4 alkyl group, C.sub.1-4 alkoxy group,
C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy group, cyano group,
nitro group, C.sub.2-6 alkanoyl group, and an
optionally-substituted amino group at each substitutable position
thereof,
[0048] provided that when V is C--R.sup.1, W is nitrogen atom, and
when V is nitrogen atom, W is C--R.sup.2,
U is carbon atom or nitrogen atom, X, Y and Z are independently
selected from the group consisting of oxygen atom, nitrogen atom,
sulfur atom and carbon atom, provided that at least one of X, Y and
Z is oxygen atom, sulfur atom, or nitrogen atom, R.sup.3 is
hydrogen atom, halogen atom, an optionally-substituted C.sub.1-6
alkyl group, an optionally-substituted C.sub.2-6 alkenyl group, an
optionally-substituted C.sub.2-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted C.sub.5-8 cycloalkenyl group, an
optionally-substituted C.sub.1-6 alkoxy group, an
optionally-substituted C.sub.1-4 haloalkyl group, an
optionally-substituted C.sub.1-4 haloalkoxy group, cyano group,
nitro group, an optionally-substituted aryl group, an
optionally-substituted heteroaryl group, an optionally-substituted
5- to 9-membered monocyclic or 7- to 10-membered bicyclic
non-aromatic unsaturated heterocyclic group, or an
optionally-substituted 4- to 9-membered monocyclic or 7- to
10-membered bicyclic saturated heterocyclic group,
[0049] wherein the C.sub.1-6 alkyl group, C.sub.2-6 alkenyl group,
C.sub.2-6 alkynyl group, C.sub.3-8 cycloalkyl group, C.sub.5-8
cycloalkenyl group, C.sub.1-6 alkoxy group, C.sub.1-4 haloalkyl
group, C.sub.1-4 haloalkoxy group, 5- to 9-membered monocyclic or
7- to 10-membered bicyclic non-aromatic unsaturated heterocyclic
group, and 4- to 9-membered monocyclic or 7- to 10-membered
bicyclic saturated heterocyclic group may be independently and
optionally substituted with one or more substituents
independently-selected from the group consisting of C.sub.1-4 alkyl
group, hydroxy group, C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl
group, C.sub.1-4 haloalkoxy group, cyano group, oxo group, aryl
group, heteroaryl group, aryloxy group, C.sub.2-6 alkanoyl group,
phenacyl group, and halogen atom at each substitutable position
thereof; and the aryl group and heteroaryl group may be
independently and optionally substituted with one or more
substituents independently-selected from the group consisting of
halogen atom, hydroxy group, C.sub.1-4 alkyl group, C.sub.1-4
alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy
group, cyano group, nitro group, C.sub.2-6 alkanoyl group, and an
optionally-substituted amino group at each substitutable position
thereof,
[0050] R.sup.4 is hydrogen atom, halogen atom, hydroxy group, an
optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.2-6 alkenyl group, an
optionally-substituted C.sub.2-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted C.sub.5-8 cycloalkenyl group, an
optionally-substituted C.sub.1-6 alkoxy group, an
optionally-substituted C.sub.1-4 haloalkyl group, an
optionally-substituted C.sub.1-4 haloalkoxy group, cyano group,
nitro group, an optionally-substituted aryl group, an
optionally-substituted heteroaryl group, or an
optionally-substituted amino group,
[0051] wherein the C.sub.1-6 alkyl group, C.sub.2-6 alkenyl group,
C.sub.2-6 alkynyl group, C.sub.3-8 cycloalkyl group, C.sub.5-8
cycloalkenyl group, C.sub.1-6 alkoxy group, C.sub.1-4 haloalkyl
group, and C.sub.1-4 haloalkoxy group may be independently and
optionally substituted with one or more substituents
independently-selected from the group consisting of C.sub.1-4 alkyl
group, hydroxy group, C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl
group, C.sub.1-4 haloalkoxy group, cyano group, oxo group, aryl
group, heteroaryl group, aryloxy group, C.sub.2-6 alkanoyl group,
phenacyl group, and halogen atom at each substitutable position
thereof; and the aryl group and heteroaryl group may be
independently and optionally substituted with one or more
substituents independently-selected from the group consisting of
halogen atom, hydroxy group, C.sub.1-4 alkyl group, C.sub.1-4
alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy
group, cyano group, nitro group, C.sub.2-6 alkanoyl group, and an
optionally-substituted amino group at each substitutable position
thereof, or
R.sup.3 and R.sup.4 may be taken together to form a saturated or
unsaturated 6- to 9-membered ring optionally comprising 1 oxygen
atom wherein the ring may be optionally substituted with one or
more substituents independently-selected from the group consisting
of C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy group,
C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy group, cyano group,
oxo group, and halogen atom at each substitutable position thereof,
and R.sup.5 and R.sup.6 are independently hydrogen atom, halogen
atom, hydroxy group, an optionally-substituted C.sub.1-6 alkyl
group, an optionally-substituted C.sub.2-6 alkenyl group, an
optionally-substituted C.sub.2-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted C.sub.5-8 cycloalkenyl group, an
optionally-substituted C.sub.1-6 alkoxy group, an
optionally-substituted C.sub.1-4 haloalkyl group, an
optionally-substituted C.sub.1-4 haloalkoxy group, cyano group,
nitro group, an optionally-substituted aryl group, an
optionally-substituted heteroaryl group, or an
optionally-substituted amino group,
[0052] wherein the C.sub.1-6 alkyl group, C.sub.2-6 alkenyl group,
C.sub.2-6 alkynyl group, C.sub.2-8 cycloalkyl group, C.sub.6-8
cycloalkenyl group, C.sub.1-6 alkoxy group, haloalkyl group, and
C.sub.1-4 haloalkoxy group may be independently and optionally
substituted with one or more substituents independently-selected
from the group consisting of C.sub.1-4 alkyl group, hydroxy group,
C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4
haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl
group, halogen atom at each substitutable position thereof; and the
aryl group and heteroaryl group may be independently and optionally
substituted with one or more substituents independently-selected
from the group consisting of halogen atom, hydroxy group, C.sub.1-4
alkyl group, C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl group,
C.sub.1-4 haloalkoxy group, cyano group, nitro group, C.sub.2-6
alkanoyl group, and an optionally-substituted amino group at each
substitutable position thereof.
Term 3
[0053] The compound of Term 2 or a pharmaceutically acceptable salt
thereof wherein the Formulae (A-1) to (A-4) may be independently
and optionally substituted with one or more substituents
independently-selected from the group consisting of C.sub.1-6 alkyl
group, C.sub.2-6 alkenyl group, C.sub.2-6 alkynyl group, hydroxy
group, C.sub.1-6 alkoxy group, and halogen atom at each
substitutable position thereof.
Term 4
[0054] The compound of any one of Terms 1 to 3 or a
pharmaceutically acceptable salt thereof wherein V is nitrogen atom
and W is C--R.sup.2.
Term 5
[0055] The compound of any one of Terms 1 to 4 or a
pharmaceutically acceptable salt thereof wherein R.sup.3 is
hydrogen atom, halogen atom, an optionally-substituted C.sub.1-6
alkyl group, an optionally-substituted C.sub.2-6 alkenyl group, an
optionally-substituted C.sub.2-6 alkynyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, or an
optionally-substituted C.sub.5-8 cycloalkenyl group.
Term 6
[0056] The compound of any one of Terms 1 to 5 or a
pharmaceutically acceptable salt thereof wherein R.sup.4 and
R.sup.5 are hydrogen atom, and R.sup.2 and R.sup.6 are
independently hydrogen atom, halogen atom, an
optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.1-6 alkoxy group, an
optionally-substituted C.sub.1-4 haloalkyl group, an
optionally-substituted C.sub.1-4 haloalkoxy group, or cyano
group.
Term 7
[0057] The compound of any one of Terms 1 to 6 or a
pharmaceutically acceptable salt thereof wherein U is carbon
atom.
Term 8
[0058] The compound of any one of Terms 1 to 7 or a
pharmaceutically acceptable salt thereof wherein X is nitrogen
atom, Y is oxygen atom, and Z is nitrogen atom.
Term 9
[0059] The compound of any one of Terms 1 to 8 or a
pharmaceutically acceptable salt thereof wherein A is (A-1), and 1
is an integer of 0 or 1.
Term 10
[0060] The compound of any one of Terms 1 to 9 or a
pharmaceutically acceptable salt thereof wherein B is (B-2), s is
an integer of 1, and r is an integer of 1 or 2.
Term 11
[0061] The compound of any one of Terms 1 to 10 which has a
chemical structure of Formula (12):
##STR00009##
or a pharmaceutically acceptable salt thereof.
Term 12
[0062] The compound of any one of Terms 1 to 11 or a
pharmaceutically acceptable salt thereof wherein D is hydrogen
atom, an optionally-substituted C.sub.1-6 alkyl group, or an
optionally-substituted C.sub.3-8 monocyclic, C.sub.7-10 bicyclic or
C.sub.7-12 tricyclic cycloalkyl group.
Term 13
[0063] The compound of any one of Terms 1 to 11 or a
pharmaceutically acceptable salt thereof wherein D is
--(CH.sub.2).sub.u--R.sup.12, and R.sup.12 is Formula
(R.sup.12-3).
Term 14
[0064] The compound of any one of Terms 1 to 11 or a
pharmaceutically acceptable salt thereof wherein D is
--(CH.sub.2).sub.u--R.sup.12, and R.sup.12 is Formula
(R.sup.12-1).
Term 15
[0065] The compound of any one of Terms 1 to 8 or a
pharmaceutically acceptable salt thereof wherein A is (A-3), is an
integer of 0, p is an integer of 0, q is an integer of either 1 or
3, and B is (B-1).
Term 16
[0066] The compound of any one of Terms 1 to 8 and 15 which has a
chemical structure of Formula (13):
##STR00010##
or a pharmaceutically acceptable salt thereof.
Term 17
[0067] The compound of any one of Terms 1 to 11 and 14 which has a
chemical structure of Formula (11):
##STR00011##
or a pharmaceutically acceptable salt thereof.
Term 18
[0068] The compound of Term 1 which is selected from the group
consisting of the following compounds or a pharmaceutically
acceptable salt thereof: [0069] (01)
1-{5-[1-(3-methoxypropyl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}-3-(propan--
2-yl)-1H-indazole, [0070] (02)
3-ethyl-1-{5-[1-(3-methoxypropyl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}-1H-
-indazole, [0071] (03)
3-cyclopropyl-1-{5-[1-(3-methoxypropyl)piperidin-4-yl]-1,2,4-oxadiazol-3--
yl}-1H-indazole, [0072] (04)
3-ethyl-6-fluoro-1-{5-[1-(3-methoxypropyl)piperidin-4-yl]-1,2,4-oxadiazol-
-3-yl}-1H-indazole, [0073] (05)
3-ethyl-7-fluoro-1-{5-[1-(3-methoxypropyl)piperidin-4-yl]-1,2,4-oxadiazol-
-3-yl}-1H-indazole, [0074] (06)
1-{5-[1-(2-methylpropyl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}-3-(propan-2-
-yl)-1H-indazole, [0075] (07)
1-{5-[1-(butan-2-yl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}-3-ethyl-1H-inda-
zole, [0076] (08)
1-{5-[1-(butan-2-yl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}-3-cyclopropyl-1-
H-indazole, [0077] (09)
3-ethyl-1-{5-[1-(2-methylpropyl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}-1H--
indazole, [0078] (10)
1-{5-[1-(cyclopropylmethyl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}-3-ethyl--
1H-indazole, [0079] (11)
1-{5-[1-(butan-2-yl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}-3-cyclobutyl-1H-
-indazole, [0080] (12)
3-cyclobutyl-1-{5-[1-(2-methylpropyl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl-
}-1H-indazole, [0081] (13)
3-(propan-2-yl)-1-[5-(1-propylpiperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-in-
dazole, [0082] (14)
3-ethyl-6-fluoro-1-(5-{1-[2-(tetrahydrofuran-2-yl)ethyl]piperidin-4-yl}-1-
,2,4-oxadiazol-3-yl)-1H-indazole, [0083] (15)
3-ethyl-1-{5-[1-(tetrahydrofuran-2-ylmethyl)piperidin-4-yl]-1,2,4-oxadiaz-
ol-3-yl}-1H-indazole, [0084] (16)
3-ethyl-6-fluoro-1-{5-[1-(tetrahydro-2H-pyran-4-ylmethyl)piperidin-4-yl]--
1,2,4-oxadiazol-3-yl}-1H-indazole, [0085] (17)
3-ethyl-6-fluoro-1-(5-{1-[2-(tetrahydro-2H-pyran-4-yl)ethyl]piperidin-4-y-
l}-1,2,4-oxadiazol-3-yl)-1H-indazole, [0086] (18)
3-ethyl-6-fluoro-1-{5-[1-(tetrahydrofuran-3-yl)piperidin-4-yl]-1,2,4-oxad-
iazol-3-yl}-1H-indazole, [0087] (19)
3-ethyl-6-fluoro-1-{5-[1-(propan-2-yl)piperidin-4-yl]-1,2,4-oxadiazol-3-y-
l}-1H-indazole, [0088] (20) methyl
4-({4-[3-(3-ethyl-6-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidi-
n-1-yl}methyl)piperidine-1-carboxylate, [0089] (21) methyl
(2S)-2-({4-[3-(3-ethyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidin-1--
yl}methyl)pyrrolidine-1-carboxylate, [0090] (22) 2-fluoroethyl
(2S)-2-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]pip-
eridin-1-yl}methyl)pyrrolidine-1-carboxylate, [0091] (23)
2-fluoroethyl
(3S)-3-({4-[3-(3-ethyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidin-1--
yl}methyl)pyrrolidine-1-carboxylate, [0092] (24)
1-[3-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piper-
idin-1-yl}methyl)azetidin-1-yl]-2-methoxyethanone, [0093] (25)
1-{4-[3-(3-ethyl-6-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-1,4'-bip-
iperidin-1'-yl}ethanone, [0094] (26)
1-{4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-1,4'-bip-
iperidin-1'-yl}ethanone, [0095] (27) methyl
4-[3-(3-ethyl-6-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-1,4'-bipipe-
ridine-1'-carboxylate, [0096] (28)
1-(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}--
1,4'-bipiperidin-1'-yl)ethanone, [0097] (29)
1-(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}--
1,4'-bipiperidin-1'-yl)-2-hydroxyethanone, [0098] (30) methyl
4-{3-[3-(3-ethyl-1,4-indazol-1-yl)-1,2,4-oxadiazol-5-yl]azetidin-1-yl}pip-
eridine-1-carboxylate, [0099] (31)
3-{4-[3-(3-ethyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}pro-
pan-1-ol, [0100] (32)
cis-N-ethyl-3-[3-(3-ethyl-6-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-
cyclobutanamine, [0101] (33)
1-[(3R)-3-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-
piperidin-1-yl}methyl)pyrrolidin-1-yl]ethanone, [0102] (34)
1-[(3R)-3-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-
piperidin-1-yl}methyl)pyrrolidin-1-yl]-2-methoxyethanone, [0103]
(35)
1-[(3R)-3-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-
piperidin-1-yl}methyl)pyrrolidin-1-yl]-2-hydroxyethanone, [0104]
(36)
1-{4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-1,4'-bip-
iperidin-1H-yl}-2-hydroxyethanone,
[0105] (37)
1-{4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-1,4'-bip-
iperidin-1'-yl}-2-methoxyethanone, [0106] (38)
4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-1'-(methyls-
ulfonyl)-1,4'-bipiperidine, [0107] (39)
1-(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}--
1,4'-bipiperidin-1'-yl)-2-methoxyethanone, [0108] (40)
1-[(3S)-3-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-
piperidin-1-yl}methyl)pyrrolidin-1-yl]ethanone, [0109] (41)
1-[(3S)-3-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-
piperidin-1-yl}methyl)pyrrolidin-1-yl]-2-methoxyethanone, [0110]
(42)
3-ethyl-7-fluoro-1-[5-(1-{[(3S)-1-(methylsulfonyl)pyrrolidin-3-yl]methyl}-
piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1,4-indazole, [0111] (43)
3-ethyl-7-fluoro-1-[5-(1-{[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]methyl}-
piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole, [0112] (44)
1-[4-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piper-
idin-1-yl}methyl)piperidin-1-yl]-2-hydroxyethanone, [0113] (45)
1-[3-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piper-
idin-1-yl}methyl)azetidin-1-yl]-2-hydroxyethanone, [0114] (46)
1-{3-[(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5--
yl}piperidin-1-yl)methyl]azetidin-1-yl}-2-methoxyethanone, [0115]
(47)
1-{3-[(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5--
yl}piperidin-1-yl)methyl]azetidin-1-yl}ethanone, [0116] (48) methyl
3-[(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-
piperidin-1-yl)methyl]azetidine-1-carboxylate, [0117] (49)
1-[3-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piper-
idin-1-yl}methyl)azetidin-1-yl]ethanone [0118] (50)
1-{(2R)-2-[(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiaz-
ol-5-yl}piperidin-1-yl)methyl]pyrrolidin-1-yl}-2-hydroxyethanone,
[0119] (51)
1-(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-
-yl}-3'-methyl-1,4'-bipiperidin-1'-yl)-2-hydroxyethanone, [0120]
(52)
1-(3-{[(3R)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadia-
zol-5-yl}methyl)pyrrolidin-1-yl]methyl}azetidin-1-yl)ethanone,
[0121] (53)
1-(3-{[(3R)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadia-
zol-5-yl}methyl)pyrrolidin-1-yl]methyl}azetidin-1-yl)-2-hydroxyethanone,
[0122] (54)
1-[(3S)-3-{[(3R)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-o-
xadiazol-5-yl}methyl)pyrrolidin-1-yl]methyl}pyrrolidin-1-yl]ethanone,
[0123] (55)
1-[(3S)-3-{[(3R)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-o-
xadiazol-5-yl}methyl)pyrrolidin-1-yl]methyl}pyrrolidin-1-yl]-2-hydroxyetha-
none, [0124] (56)
1-[(3R)-3-{[(3R)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-o-
xadiazol-5-yl}methyl)pyrrolidin-1-yl]methyl}pyrrolidin-1-yl]-2-hydroxyetha-
none, [0125] (57)
1-[(2S)-2-{[(3S)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-o-
xadiazol-5-yl}methyl)pyrrolidin-1-yl]methyl}pyrrolidin-1-yl]-2-hydroxyetha-
none, [0126] (58)
1-[(2R)-2-{[(3S)-3-({3-[7-fluoro-3-(propan-2-yl)-1,4-indazol-1-yl]-1,2,4--
oxadiazol-5-yl}methyl)pyrrolidin-1-yl]methyl}pyrrolidin-1-yl]-2-hydroxyeth-
anone, [0127] (59)
1-[(3S)-3-{[(3S)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-o-
xadiazol-5-yl}methyl)pyrrolidin-1-yl]methyl}pyrrolidin-1-yl]-2-hydroxyetha-
none, [0128] (60)
1-[(3R)-3-{[(3S)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-o-
xadiazol-5-yl}methyl)pyrrolidin-1-yl]methyl}pyrrolidin-1-yl]-2-hydroxyetha-
none, [0129] (61)
1-{4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-4'-methy-
l-1,4'-bipiperidin-1'-yl}-2-hydroxyethanon, [0130] (62)
1-{4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-4'-methy-
l-1,4'-bipiperidin-1'-yl}-2-methoxyethanone, [0131] (63)
(2S)-1-{4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-4'--
methyl-1,4'-bipiperidin-1'-yl}-2-hydroxypropan-1-one, [0132] (64)
1-[(3S)-3-({4-[3-(3-ethyl-7-fluoro-1,4-indazol-1-yl)-1,2,4-oxadiazol-5-yl-
]piperidin-1-yl}methyl)pyrrolidin-1-yl]-2-hydroxyethanone, [0133]
(65)
1-[(2S)-2-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-
piperidin-1-yl}methyl)pyrrolidin-1-yl]-2-hydroxyethanone, [0134]
(66)
1-{4-[(3S)-3-{[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-
methyl}pyrrolidin-1-yl]piperidin-1-yl}ethanone, [0135] (67)
1-{4-[(3R)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiaz-
ol-5-yl}methyl)pyrrolidin-1-yl]piperidin-1-yl}-2-methoxyethanone,
[0136] (68)
1-(3-{[(3R)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-o-
xadiazol-5-yl}methyl)pyrrolidin-1-yl]methyl}azetidin-1-yl)-2-methoxyethano-
ne, [0137] (69)
1-[(3S)-3-{[(3R)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-o-
xadiazol-5-yl}methyl)pyrrolidin-1-yl]methyl}pyrrolidin-1-yl]-2-methoxyetha-
none, [0138] (70)
1-[(3R)-3-{[(3R)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-o-
xadiazol-5-yl}methyl)pyrrolidin-1-yl]methyl}pyrrolidin-1-yl]-2-methoxyetha-
none, [0139] (71)
1-{4-[(3S)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiaz-
ol-5-yl}methyl)pyrrolidin-1-yl]piperidin-1-yl}-2-methoxyethanone,
[0140] (72)
1-(3-{[(3S)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-o-
xadiazol-5-yl}methyl)pyrrolidin-1-yl]methyl}azetidin-1-yl)-2-methoxyethano-
ne, [0141] (73)
1-[(3S)-3-{[(3S)-3-({3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-o-
xadiazol-5-yl}methyl)pyrrolidin-1-yl]methyl}pyrrolidin-1-yl]-2-methoxyetha-
none, and [0142] (74)
1-(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}--
3'-methyl-1,4'-bipiperidin-1'-yl)ethanone.
Term 19
[0143] A pharmaceutical composition comprising the compound of any
one of Terms 1 to 18 or a pharmaceutically acceptable salt
thereof.
Term 20
[0144] A serotonin-4 receptor agonist comprising the compound of
any one of Terms 1 to 18 or a pharmaceutically acceptable salt
thereof as an active ingredient.
Term 21
[0145] A medicament for treating Alzheimer-type dementia comprising
the compound of any one of Terms 1 to 18 or a pharmaceutically
acceptable salt thereof as an active ingredient.
Term 22
[0146] A method for treating a disease associated with serotonin-4
receptor comprising administering a therapeutically effective
amount of the compound of any one of Terms 1 to 18 or a
pharmaceutically acceptable salt thereof to a patient in need
thereof.
Term 23
[0147] A method for treating Alzheimer-type dementia comprising
administering a therapeutically effective amount of the compound of
any one of Terms 1 to 18 or a pharmaceutically acceptable salt
thereof to a patient in need thereof.
Effects of Invention
[0148] The present invention can provide compounds which act as an
agonist or a partial agonist to a serotonin-4 receptor
(hereinafter, optionally referred to as a 5-HT.sub.4 receptor), and
thus can provide a medicament for treating or preventing diseases
or symptoms associated with serotonin-4 receptor. The diseases or
symptoms suggested to be associated with serotonin-4 receptor
include the following (i) to (v):
(i) neuropsychiatric diseases such as Alzheimer-type dementia, Lewy
body dementia, vascular dementia, depression, posttraumatic stress
disorder (PTSD), memory impairment, anxiety, and schizophrenia;
(ii) digestive system diseases such as irritable bowel syndrome,
atonic constipation, habitual constipation, chronic constipation,
constipation induced by drugs (e.g. morphine and antipsychotic
drugs), constipation associated with Parkinson's disease,
constipation associated with multiple sclerosis, constipation
associated with diabetes mellitus, and constipation or dyschezia
caused by contrast materials taken as a pretreatment for endoscopic
examinations or barium enema X-ray examinations; (iii) digestive
system diseases such as functional dyspepsia, acute/chronic
gastritis, reflux esophagitis, gastric ulcer, duodenal ulcer,
gastric neurosis, postoperative paralytic ileus, senile ileus,
non-erosive reflux disease, NSAID ulcer, diabetic gastroparesis,
postgastrectomy syndrome, and intestinal pseudo-obstruction; (iv)
digestive system symptoms such as the digestive system diseases
mentioned in the above (ii) and (iii), scleroderma, diabetes
mellitus, anorexia in esophageal/biliary-tract diseases, nausea,
emesis, bloating, epigastric discomfort, abdominal pain, heartburn,
and belching; and (v) urinary system diseases associated with
dysuria such as urinary tract obstruction and prostatic
hyperplasia.
[0149] The present compound is useful as a medicament for treating
or preventing especially the neuropsychiatric diseases such as
Alzheimer-type dementia mentioned in the above (i) because the
compound shows an excellent 5-HT.sub.4 receptor agonist activity
and brain penetration.
DESCRIPTION OF EMBODIMENTS
[0150] Hereinafter, the present invention is explained in more
detail.
[0151] The "optionally substituted" or "substituted" group defined
herein means that, unless otherwise indicated, the number of
substituents is unlimited as long as possible, i.e. one or more
substituents. Furthermore, unless otherwise noted, the definitions
for each group may be also applied to a part of other groups or a
substituent of other groups.
[0152] The terms used herein are set forth as below.
[0153] The "C.sub.1-6 alkyl group" used herein includes a straight-
or branched-chain alkyl group having 1 to 6 carbon atoms; and
specifically methyl group, ethyl group, propyl group, isopropyl
group, butyl group, isobutyl group, sec-butyl group, tert-butyl
group, pentyl group, hexyl group, etc. The O.sub.1-6 alkyl group
includes preferably C.sub.1-4 alkyl group; and specifically methyl
group, ethyl group, propyl group, isopropyl group, butyl group,
isobutyl group, sec-butyl group, and tert-butyl group.
[0154] The "C.sub.2-6 alkenyl group" used herein includes a
straight- or branched-chain alkenyl group having 2 to 6 carbon
atoms and 1 to 2 double bonds. The C.sub.2-6 alkenyl group includes
specifically ethenyl group, 1-propenyl group, 1-methylvinyl group,
2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl
group, 2-methyl-1-propenyl group, 2-methyl-2-propenyl group,
1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl
group, 2-methyl-1-butenyl group, 2-methyl-2-butenyl group,
2-methyl-3-butenyl group, 1-hexenyl group, 2-hexenyl group,
3-hexenyl group, 4-hexenyl group, 5-hexenyl group,
2-methyl-1-pentenyl group, 2-propyl-2-propenyl group,
1-ethyl-2-methyl-2-propenyl group, 1-methyl-3-methyl-3-butenyl
group, 4-methyl-4-pentenyl group, 1,3-butadienyl group,
1,5-hexadienyl group, etc.; and preferably ethenyl group,
1-propenyl group, 1-methylvinyl group, 2-propenyl group, 1-butenyl
group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group,
and 2-methyl-2-propenyl group.
[0155] The "C.sub.2-6 alkynyl group" used herein includes a
straight- or branched-chain alkynyl group having 2 to 6 carbon
atoms and 1 to 2 triple bonds, and more preferably 1 triple bond.
The C.sub.2-6 alkynyl group includes specifically ethynyl group,
1-propynyl group, 2-propynyl group, 1-butynyl group,
1-methyl-2-propynyl group, 3-butynyl group, 2-butynyl group,
1-pentynyl group, 1-ethyl-2-propynyl group, 4-pentynyl group,
3-pentynyl group, 2-pentynyl group, 1-methyl-2-butynyl group,
1-hexynyl group, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group,
5-hexynyl group, etc; and preferably ethynyl group, 1-propynyl
group, 2-propynyl group, 1-butynyl group, 1-methyl-2-propynyl
group, 3-butynyl group, 2-butynyl group, 1-pentynyl group,
1-ethyl-2-propynyl group, 4-pentynyl group, 3-pentynyl group,
2-pentynyl group, and 1-methyl-2-butynyl group.
[0156] The "C.sub.1-6 alkoxy group" used herein includes a
straight- or branched-chain alkoxy group having 1 to 6 carbon
atoms. The C.sub.1-6 alkoxy group includes specifically methoxy
group, ethoxy group, propoxy group, isopropoxy group, butoxy group,
isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy
group, hexyloxy group etc.; and preferably methoxy group, ethoxy
group, propoxy group, isopropoxy group, butoxy group, isobutoxy
group, sec-butoxy group, and tert-butoxy group.
[0157] The "halogen atom" used herein includes fluorine atom,
chlorine atom, bromine atom and iodine atom; preferably fluorine
atom and chlorine atom; and more preferably fluorine atom.
[0158] The "C.sub.3-6 alkenyl group" used herein includes a
straight- or branched-chain alkenyl group having 3 to 6 carbon
atoms and 1 to 2 double bonds. The C.sub.3-6 alkenyl group includes
specifically 1-propenyl group, 1-methylvinyl group, 2-propenyl
group, 1-butenyl group, 2-butenyl group, 3-butenyl group,
2-methyl-1-propenyl group, 2-methyl-2-propenyl group, 1-pentenyl
group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group,
2-methyl-1-butenyl group, 2-methyl-2-butenyl group,
2-methyl-3-butenyl group, 1-hexenyl group, 2-hexenyl group,
3-hexenyl group, 4-hexenyl group, 5-hexenyl group,
2-methyl-1-pentenyl group, 2-propyl-2-propenyl group,
1-ethyl-2-methyl-2-propenyl group, 1-methyl-3-methyl-3-butenyl
group, 4-methyl-4-pentenyl group, 1,3-butadienyl group,
1,5-hexadienyl group, etc.; and preferably 1-propenyl group,
1-methylvinyl group, 2-propenyl group, 1-butenyl group, 2-butenyl
group, 3-butenyl group, 2-methyl-1-propenyl group,
2-methyl-2-propenyl group, 1-pentenyl group, 2-pentenyl group,
3-pentenyl group, 4-pentenyl group, 2-methyl-1-butenyl group,
2-methyl-2-butenyl group, and 2-methyl-3-butenyl group.
[0159] The "C.sub.3-6 alkynyl group" used herein includes a
straight- or branched-chain alkynyl group having 3 to 6 carbon
atoms and 1 to 2 triple bonds, and more preferably 1 triple bond.
The C.sub.3-6 alkynyl group includes specifically 1-propynyl group,
2-propynyl group, 1-butynyl group, 1-methyl-2-propynyl group,
3-butynyl group, 2-butynyl group, 1-pentynyl group,
1-ethyl-2-propynyl group, 4-pentynyl group, 3-pentynyl group,
2-pentynyl group, 1-methyl-2-butynyl group, 1-hexynyl group,
2-hexynyl group, 3-hexynyl group, 4-hexynyl group, 5-hexynyl group,
etc; and preferably 1-propynyl group, 2-propynyl group, 1-butynyl
group, 1-methyl-2-propynyl group, 3-butynyl group, 2-butynyl group,
1-pentynyl group, 1-ethyl-2-propynyl group, 4-pentynyl group,
3-pentynyl group, 2-pentynyl group, and 1-methyl-2-butynyl
group.
[0160] The "C.sub.3-8 cycloalkyl group" used herein includes a 3-
to 8-membered cycloalkyl group; specifically cyclopropyl group,
cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl
group, cyclooctyl group, etc.; and preferably cyclopropyl group,
cyclobutyl group, cyclopentyl group, and cyclohexyl group.
[0161] The "C.sub.5-8 cycloalkenyl group" used herein includes a 5-
to 8-membered cycloalkenyl group; specifically cyclopentenyl group,
3-cyclopentenyl group, 4-cyclopentenyl group, 1-cyclohexenyl group,
3-cyclohexenyl group, 4-cyclohexenyl group, 1-cycloheptenyl group,
3-cycloheptenyl group, 4-cycloheptenyl group, 5-cycloheptenyl
group, 1-cyclooctenyl group, 3-cyclooctenyl group, 4-cyclooctenyl
group, 5-cyclooctenyl group, etc.; and preferably 1-cyclopentenyl
group, 3-cyclopentenyl group, 4-cyclopentenyl group, 1-cyclohexenyl
group, 3-cyclohexenyl group, and 4-cyclohexenyl group.
[0162] The "aryl group" used herein includes a 6- to 10-membered
monocyclic or bicyclic aryl group; and specifically phenyl group,
1-naphthyl group, 2-naphthyl group, etc.
[0163] The "heteroaryl group" used herein includes a 5- to
10-membered monocyclic or bicyclic heteroaryl group comprising 1 to
4 heteroatoms selected from the group consisting of 1 to 3 nitrogen
atoms, 1 oxygen atom and 1 sulfur atom. The monocyclic heteroaryl
group includes specifically pyrrolyl group, imidazolyl group,
triazolyl group, tetrazolyl group, furyl group, thienyl group,
oxazolyl group, thiazolyl group, pyridyl group, pyrimidinyl group,
pyrazinyl group, pyridazinyl group, triazinyl group, etc.; and
preferably pyrrolyl group, imidazolyl group, triazolyl group,
tetrazolyl group, furyl group, thienyl group, oxazolyl group,
pyridyl group, pyrimidinyl group, pyrazinyl group, and pyridazinyl
group.
[0164] The bicyclic heteroaryl group includes indolyl group,
benzofuryl group, benzothienyl group, quinolinyl group,
benzisoxazolyl group, etc. The binding site of the heteroaryl group
is not limited and may be any carbon atom or nitrogen atom therein
as long as the bond is chemically stable. The heteroaryl group
includes preferably indolyl group and quinolinyl group.
[0165] The "5- to 9-membered monocyclic or 7- to 10-membered
bicyclic non-aromatic unsaturated heterocyclic group" used herein
includes a 5- to 9-membered monocyclic or 7- to 10-membered
bicyclic non-aromatic unsaturated heterocyclic group comprising 1
to 4 heteroatoms selected from the group consisting of 1 to 3
nitrogen atoms, 1 oxygen atom and 1 sulfur atom. The monocyclic
non-aromatic unsaturated heterocyclic group includes a 5-membered
non-aromatic unsaturated heterocyclic group having 1 double bond
and a 6- or 7-membered non-aromatic unsaturated heterocyclic group
having 1 or 2 double bonds; and specifically pyrrolinyl group,
2,5-dihydrofuryl group, etc.
[0166] The bicyclic non-aromatic unsaturated heterocyclic group
includes a 7- to 10-membered non-aromatic unsaturated heterocyclic
group which can be obtained by replacing one or more double bonds
of the bicyclic heteroaryl group with single bonds; and
specifically 2,3-dihydrobenzofuryl group, 2,3-dihydrobenzothienyl
group, etc.
[0167] The binding site of the non-aromatic unsaturated
heterocyclic group is not limited and may be any carbon atom or
nitrogen atom therein as long as the bond is chemically stable.
[0168] The "4- to 9-membered monocyclic or 7- to 10-membered
bicyclic saturated heterocyclic group" used herein includes a 4- to
9-membered monocyclic or 7- to 10-membered bicyclic saturated
heterocyclic group comprising 1 to 4 heteroatoms selected from the
group consisting of 1 to 4 nitrogen atoms, 1 oxygen atom and 1
sulfur atom. The monocyclic saturated heterocyclic group includes
specifically azetidinyl group, pyrrolidinyl group, tetrahydrofuryl
group, tetrahydrothienyl group, piperazinyl group, piperidinyl
group, morpholinyl group, thiomorpholinyl group, tetrahydropyranyl
group, hexahydroazepinyl group, 1,4-hexahydrooxazepinyl group,
1,4-hexahydrodiazepinyl group, etc.; and preferably azetidinyl
group, pyrrolidinyl group, tetrahydrofuryl group, piperazinyl
group, piperidinyl group, morpholinyl group, and tetrahydropyranyl
group. The bicyclic saturated heterocyclic group includes a 7- to
10-membered saturated heterocyclic group; and specifically
quinuclidinyl group, etc.
[0169] Any carbon atom in the saturated heterocyclic group may be
substituted with oxo group. The saturated heterocyclic group
substituted with oxo group includes specifically 2-oxopyrrolidinyl
group, 2-oxotetrahydrofuryl group, etc.
[0170] The binding site of the saturated heterocyclic group is not
limited and may be any carbon atom or nitrogen atom therein as long
as the bond is chemically stable.
[0171] The "C.sub.1-4 alkyl group" used herein includes a straight-
or branched-chain alkyl group having 1 to 4 carbon atoms;
specifically methyl group, ethyl group, propyl group, isopropyl
group, butyl group, isobutyl group, sec-butyl group, tert-butyl
group etc.; and preferably methyl group, ethyl group, propyl group,
and isopropyl group.
[0172] The "C.sub.1-4 alkoxy group" used herein includes a
straight- or branched-chain alkoxy group having 1 to 4 carbon
atoms; specifically methoxy group, ethoxy group, propoxy group,
isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group,
tert-butoxy group etc.; and preferably methoxy group, ethoxy group,
propoxy group, isopropoxy group, and tert-butoxy group.
[0173] The "C.sub.1-4 haloalkoxy group" used herein includes an
alkoxy group having 1 to 4 carbon atoms which is substituted with
the same or a different 1 to 5 halogen atoms; specifically
fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group,
pentafluoroethoxy group, 2-fluoroethoxy group, 2,2-difluoroethoxy
group, etc.; and preferably trifluoromethoxy group and
pentafluoroethoxy group.
[0174] The "C.sub.1-4 haloalkyl group" used herein includes an
alkyl group having 1 to 4 carbon atoms which is substituted with
the same or a different 1 to 5 halogen atoms; specifically
fluoromethyl group, difluoromethyl group, trifluoromethyl group,
2-fluoroethyl group, 2,2-difluoroethyl group, 4-fluoro butyl group,
etc.; and preferably fluoromethyl group, difluoromethyl group, and
trifluoromethyl group.
[0175] The "aryloxy group" used herein includes an aryloxy group
having 6 to 10 carbon atoms; and specifically phenoxy group,
naphthoxy group etc. straight- or branched-chain alkanoyl group
having 2 to 6 carbon atoms; specifically acetyl group, propanoyl
group, butanoyl group, 2-methylpropanoyl group, pentanoyl group,
3-methylbutanoyl group, 2-methylbutanoyl group, hexanoyl group,
etc.; and preferably acetyl group, propanoyl group, butanoyl group,
and 2-methylpropanoyl group.
[0176] The "optionally-substituted amino group" used herein
includes, for example, amino, mono- or di-substituted amino, and 4-
to 7-membered cyclic amino. The substituents of the "mono- or
di-substituted amino" includes, for example, "C.sub.1-6 alkyl",
"C.sub.3-7 cycloalkyl", "C.sub.3-7 cycloalkyl C.sub.1-4 alkyl",
etc.
[0177] The "monosubstituted amino" includes, for example, "mono
C.sub.1-6 alkylamino" such as methylamino, ethylamino, propylamino,
1-methylethylamino, butylamino, 2-methylpropylamino,
1-methylpropylamino, and 1,1-dimethylethylamino; "C.sub.3-7
cycloalkyl amino" such as cyclopropylamino, cyclobutylamino,
cyclopentylamino, cyclohexylamino, and cycloheptylamino; and
"(C.sub.3-7 cycloalkyl C.sub.1-4 alkyl)amino" such as
cyclopropylmethyl-amino, cyclobutylmethylamino,
cyclopentylmethylamino, cyclohexylmethylamino, and
cycloheptylmethylamino.
[0178] The "di-substituted amino" includes, for example,
"di-C.sub.1-6 alkylamino" such as dimethylamino, diethylamino,
dipropylamino, di-1-methylethylamino, dibutylamino,
di-2-methylpropylamino, di-1-methylpropylamino, and
di-1,1-dimethylethylamino; and "N"-(C.sub.1-6 alkyl)-N--(C.sub.3-7
cycloalkyl)amino" such as methylcyclopropylamino,
methyl-cyclobutylamino, methylcyclopentylamino,
methylcyclo-hexylamino, and methylcycloheptylamino.
[0179] The "4- to 7-membered cyclic amino group" includes, for
example, a 4- to 7-membered monocyclic amino group comprising
additional 0 to 2 heteroatoms independently-selected from the group
consisting of nitrogen atom, oxygen atom and sulfur atom; and the
binding site thereof is the nitrogen atom in the ring. The
optionally-substituted amino group includes, for example,
azetidino, pyrrolidino, piperazino, piperidino, morpholino,
thiomorpholino, azepano, and oxoazepano; preferably amino,
methylamino, ethylamino, cyclopropylamino, cyclobutylamino,
dimethylamino, di-1-methylethylamino, methylcyclopropylamino,
azetidino, pyrrolidino, piperazino, piperidino, and morpholino; and
more preferably amino, methylamino, dimethylamino, azetidino,
pyrrolidino, and piperidino.
[0180] The "saturated or unsaturated 4- to 9-membered monocyclic or
7- to 10-membered bicyclic nitrogen-containing heterocyclic group
comprising the adjacent nitrogen atom and additional 0 to 2
heteroatoms independently-selected from the group consisting of 1
to 2 nitrogen atoms, 1 oxygen atom and 1 sulfur atom" used herein
includes specifically azetidinyl group, pyrrolidinyl group,
piperazinyl group, piperidinyl group, morpholinyl group,
thiomorpholinyl group, hexahydroazepinyl group,
1,4-hexahydrooxazepinyl group, 1,4-hexahydrodiazepinyl group,
indolinyl group, isoindolinyl group, 1,2,3,4-tetrahydroquinolinyl
group, 1,2,3,4-tetrahydroisoquinolinyl group,
1,2,3,4-tetrahydroquinoxalinyl group, 3,4-dihydrobenzo-1,4-oxadinyl
group, 3,4-dihydrobenzo-1,4-thiadinyl group,
3-azabicyclo[3.2.0]heptanyl group, octahydroisoindolyl group,
octahydroindolyl group, decahydroquinolinyl group,
decahydroisoquinolinyl group, decahydroquinoxalinyl group,
octahydrobenzo-1,4-oxadinyl group, octahydrobenzo-1,4-thiadinyl
group, etc.; preferably azetidinyl group, pyrrolidinyl group,
piperazinyl group, piperidinyl group, morpholinyl group,
hexahydroazepinyl group, 1,4-hexahydrooxazepinyl group, indolinyl
group, isoindolinyl group, 1,2,3,4-tetrahydroquinolinyl group,
1,2,3,4-tetrahydroisoquinolinyl group, and
3,4-dihydrobenzo-1,4-oxadinyl group; and more preferably
pyrrolidinyl group, piperazinyl group, piperidinyl group, and
morpholinyl group.
[0181] The "saturated or unsaturated 3- to 8-membered ring that may
comprise 1 oxygen atom" used herein includes specifically
cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane
ring, cycloheptane ring, cyclooctane ring, oxetane ring,
tetrahydrofuran ring, tetrahydropyran ring, oxepane ring, benzene
ring, etc.; and preferably cyclopropane ring, cyclobutane ring,
cyclopentane ring, and cyclohexane ring.
[0182] The "bicyclic or a spiro compound in which the
above-mentioned ring is attached with the pair of R.sup.10 and
R.sup.11, or R.sup.10' and R.sup.11'" used herein includes
specifically indoline, isoindoline, 1,2,3,4-tetrahydroquinoline,
1,2,3,4-tetra-hydroisoquinoline, 3-azabicyclo[3.2.0]heptane,
7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane,
2-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.1]heptane,
8-azabicyclo[3.2.1]octane, 2-azabicyclo[2.2.2]octane,
3-azabicyclo[3.2.1]octane, octahydroisoindone, octahydroindoline,
decahydroquinoline, decahydroisoquinoline,
octahydrocyclopenta[b]pyrrole, octahydrocyclopenta[c]pyrrole,
2-oxa-7-azaspiro[3.5]nonane, 2-oxa-8-azaspiro[4.5]decane, etc.;
preferably indoline, isoindoline, 1,2,3,4-tetrahydroquinoline,
1,2,3,4-tetrahydroisoquinoline, 3-azabicyclo-[3.2.0]heptane,
7-azabicyclo[2.2.1]heptane, 6-azabicyclo-[3.1.1]heptane,
2-azabicyclo[2.2.1]heptane, 3-azabicyclo-[3.1.1]heptane,
8-azabicyclo[3.2.1]octane, and 2-azabicyclo[2.2.2]octane,
3-azabicyclo[3.2.1]octane; and more preferably
7-azabicyclo[2.2.1]heptane, 8-azabicyclo[3.2.1]-octane, and
3-azabicyclo[3.2.1]octane.
[0183] The "C.sub.3-8 monocyclic, C.sub.7-10 bicyclic or C.sub.7-12
tricyclic cycloalkyl group" used herein includes 3- to 8-membered
monocyclic cycloalkyl group, 7- to 10-membered bicyclic cycloalkyl
group, or 7- to 12-membered tricyclic cycloalkyl group,
respectively.
[0184] The monocyclic cycloalkyl group used herein includes
specifically cyclopropyl group, cyclobutyl group, cyclopentyl
group, cyclohexyl group, cycloheptyl group, cyclooctyl group, etc.;
and preferably cyclopropyl group, cyclobutyl group, cyclopentyl
group, and cyclohexyl group.
[0185] The bicyclic cycloalkyl group used herein includes
specifically octahydropentalenyl group, octahydro-1H-indenyl group,
bicyclo[2.2.1]heptyl group, bicyclo[2.2.2]octyl group,
bicyclo[4.2.0]octyl group, decahydronaphthalenyl group, etc.; and
preferably bicyclo[2.2.1]heptyl group and bicyclo[2.2.2]octyl
group.
[0186] The tricyclic cycloalkyl group used herein includes
specifically adamantyl group, etc.
[0187] The "C.sub.5-8 monocyclic or C.sub.7-10 bicyclic
cycloalkenyl group" used herein includes 5- to 8-membered
monocyclic cycloalkenyl group or 7- to 10-membered bicyclic
cycloalkenyl group, respectively.
[0188] The monocyclic cycloalkenyl group used herein includes
specifically 1-cyclopentenyl group, 3-cyclopentenyl group,
4-cyclopentenyl group, 1-cyclohexenyl group, 3-cyclohexenyl group,
4-cyclohexenyl group, 1-cycloheptenyl group, 3-cycloheptenyl group,
4-cycloheptenyl group, 5-cycloheptenyl group, 1-cyclooctenyl group,
3-cyclooctenyl group, 4-cyclooctenyl group, 5-cyclooctenyl group,
etc; preferably 1-cyclopentenyl group, 3-cyclopentenyl group,
4-cyclopentenyl group, 1-cyclohexenyl group, 3-cyclohexenyl group,
and 4-cyclohexenyl group.
[0189] The bicyclic cycloalkenyl group used herein includes
specifically bicyclo[2.2.1]hept-2-enyl group,
bicyclo-[2.2.2]oct-2-enyl group, etc.
[0190] Regarding the "saturated or unsaturated 4- to 8-membered
monocyclic nitrogen-containing heterocyclic group comprising the
adjacent nitrogen atom and additional 0 to 2 heteroatoms
independently-selected from the group consisting of 1 to 2 nitrogen
atoms, 1 oxygen atom and 1 sulfur atom" used herein, the saturated
monocyclic nitrogen-containing heterocyclic group includes
specifically azetidinyl group, pyrrolidinyl group, piperazinyl
group, piperidinyl group, morpholinyl group, thiomorpholinyl group,
hexahydroazepinyl group, 1,4-hexahydrooxazepinyl group, etc.; and
preferably azetidinyl group, pyrrolidinyl group, piperazinyl group,
piperidinyl group, and morpholinyl group.
[0191] The unsaturated monocyclic nitrogen-containing heterocyclic
group includes specifically pyrrolyl group, imidazolyl group,
triazolyl group, tetrazolyl group, 1,2,3,6-tetrahydropyridyl group,
2,5-dihydro-1H-pyrrolyl group, etc.
[0192] The "C.sub.1-6 alkoxycarbonyl group" used herein includes a
carbonyl group having a straight- or branched-chain alkoxy group
having 1 to 6 carbon atoms; specifically methoxycarbonyl group,
ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl
group, butoxycarbonyl group, isobutoxycarbonyl group,
sec-butoxycarbonyl group, tert-butoxycarbonyl group,
pentyloxycarbonyl group, hexyloxycarbonyl group etc.; and
preferably methoxycarbonyl group, ethoxycarbonyl group,
propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl
group, isobutoxycarbonyl group, sec-butoxycarbonyl group, and
tert-butoxycarbonyl group.
[0193] The "C.sub.1-6 alkylsulfonyl group" used herein includes a
straight- or branched-chain alkylsulfonyl group having 1 to 6
carbon atoms; specifically methylsulfonyl group, ethylsulfonyl
group, propylsulfonyl group, isopropyl sulfonyl group,
butylsulfonyl group, isobutylsulfonyl group, sec-butylsulfonyl
group, tert-butylsulfonyl group, pentylsulfonyl group,
hexylsulfonyl group, etc.; and preferably methylsulfonyl group,
ethylsulfonyl group, propylsulfonyl group, isopropyl sulfonyl
group, butylsulfonyl group, isobutylsulfonyl group,
sec-butylsulfonyl group, and tert-butylsulfonyl group.
[0194] The "saturated or unsaturated 6- to 9-membered ring
optionally comprising 1 oxygen atom formed by taking R.sup.3 and
R.sup.4 together" used herein includes specifically the 6- to
9-membered ring of the following Formulae (E-1) to (E-16):
##STR00012## ##STR00013## ##STR00014##
and the like; preferably Formulae (E-1), (E-4), (E-5), (E-8),
(E-9), (E-10), and (E-14).
[0195] The "5-membered heteroaryl which is the substructure of
Formula (1), i.e. the following Formula (F):
##STR00015##
wherein U is carbon atom or nitrogen atom; and X, Y and Z are
independently selected from the group consisting of oxygen atom,
nitrogen atom, sulfur atom and carbon atom, provided that at least
one of X, Y and Z is oxygen atom, sulfur atom, or nitrogen atom"
includes heteroaryl of the following Formulae (F-1) to (F-16):
##STR00016## ##STR00017##
The binding site of the heteroaryl is not limited and may be any
carbon atom or nitrogen atom therein as long as the bond is
chemically stable. The heteroaryl includes preferably Formulae
(F-10) to (F-13), and more preferably Formulae (F-10) to
(F-11).
[0196] Hereinafter, each group of the present invention is
explained.
[0197] The "A" used herein includes preferably Formula (A-1) and
Formula (A-3), and more preferably Formula (A-1).
[0198] The "B" used herein includes preferably Formula (B-1) and
Formula (B-2), and more preferably Formula (B-2).
[0199] The "R.sup.8, R.sup.9 and D" used herein independently
include preferably hydrogen atom, an optionally-substituted
C.sub.1-6 alkyl group, an optionally-substituted C.sub.3-8
monocyclic, C.sub.7-10 bicyclic or C.sub.7-12 tricyclic cycloalkyl
group, and --(CH.sub.2).sub.u--R.sup.12.
[0200] The "R.sup.13" used herein includes preferably Formula
(R.sup.12-1), Formula (R.sup.12-3), and Formula (R.sup.12-5).
[0201] The "R.sup.13" used herein includes preferably hydrogen
atom, an optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, --COR.sup.16,
SO.sub.2R.sup.16, COOR.sup.16, and --CONR.sup.19R.sup.20; more
preferably an optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, --COR.sup.16,
--SO.sub.2R.sup.16, and --COOR.sup.16; and even more preferably
--COR.sup.16, --SO.sub.2R.sup.16, and --COOR.sup.16.
[0202] The "R.sup.16" used herein includes preferably an
optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.3-8 cycloalkyl group, an
optionally-substituted aryl group, and an optionally-substituted
heteroaryl group; and more preferably an optionally-substituted
C.sub.1-6 alkyl group and an optionally-substituted C.sub.3-8
cycloalkyl group.
[0203] The "R.sup.14 and R.sup.15" used herein independently
include preferably hydrogen atom, an optionally-substituted
C.sub.1-6 alkyl group, an optionally-substituted C.sub.3-8
cycloalkyl group, an optionally-substituted aryl group, and an
optionally-substituted heteroaryl group; and more preferably an
optionally-substituted C.sub.1-6 alkyl group and an
optionally-substituted C.sub.3-8 cycloalkyl group.
[0204] The "R.sup.1" used herein includes preferably hydrogen atom,
halogen atom, an optionally-substituted C.sub.1-6 alkyl group, and
an optionally-substituted C.sub.3-8 cycloalkyl group; and more
preferably hydrogen atom.
[0205] The "R.sup.2" used herein includes preferably hydrogen atom,
halogen atom, hydroxy group, an optionally-substituted C.sub.1-6
alkyl group, an optionally-substituted C.sub.3-8 cycloalkyl group,
an optionally-substituted C.sub.1-6 alkoxy group, an
optionally-substituted haloalkyl group, an optionally-substituted
C.sub.1-4 haloalkoxy group, cyano group, nitro group, an
optionally-substituted aryl group, an optionally-substituted
heteroaryl group, and an optionally-substituted amino group; more
preferably hydrogen atom, halogen atom, an optionally-substituted
C.sub.1-6 alkyl group, an optionally-substituted C.sub.1-6 alkoxy
group, an optionally-substituted C.sub.1-4 haloalkyl group, and an
optionally-substituted C.sub.1-4 haloalkoxy group; and even more
preferably hydrogen atom, halogen atom, and an
optionally-substituted C.sub.1-6 alkyl group.
[0206] The "R.sup.3" used herein includes preferably hydrogen atom,
halogen atom, an optionally-substituted C.sub.1-6 alkyl group, and
an optionally-substituted C.sub.3-8 cycloalkyl group; and more
preferably hydrogen atom, halogen atom, and an
optionally-substituted C.sub.1-6 alkyl group.
[0207] The "R.sup.4" used herein includes preferably hydrogen atom,
halogen atom, hydroxy group, an optionally-substituted C.sub.1-6
alkyl group, an optionally-substituted C.sub.3-8 cycloalkyl group,
an optionally-substituted C.sub.1-6 alkoxy group, an
optionally-substituted C.sub.1-4 haloalkyl group, an
optionally-substituted C.sub.1-4 haloalkoxy group, cyano group,
nitro group, an optionally-substituted aryl group, an
optionally-substituted heteroaryl group, and an
optionally-substituted amino group; more preferably hydrogen atom,
halogen atom, an optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.1-6 alkoxy group, an
optionally-substituted C.sub.1-4 haloalkyl group, and an
optionally-substituted C.sub.1-4 haloalkoxy group; and even more
preferably hydrogen atom, halogen atom, and an
optionally-substituted C.sub.1-6 alkyl group.
[0208] The "R.sup.5" used herein includes preferably hydrogen atom,
halogen atom, hydroxy group, an optionally-substituted C.sub.1-6
alkyl group, an optionally-substituted O.sub.3-8 cycloalkyl group,
an optionally-substituted C.sub.1-6 alkoxy group, an
optionally-substituted C.sub.1-4 haloalkyl group, an
optionally-substituted C.sub.1-4 haloalkoxy group, cyano group,
nitro group, an optionally-substituted aryl group, an
optionally-substituted heteroaryl group, and an
optionally-substituted amino group; more preferably hydrogen atom,
halogen atom, an optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.1-6 alkoxy group, an
optionally-substituted C.sub.1-4 haloalkyl group, and an
optionally-substituted C.sub.1-4 haloalkoxy group; and even more
preferably hydrogen atom, halogen atom, and an
optionally-substituted C.sub.1-6 alkyl group.
[0209] The "R.sup.6" used herein includes preferably hydrogen atom,
halogen atom, hydroxy group, an optionally-substituted C.sub.1-6
alkyl group, an optionally-substituted C.sub.3-8 cycloalkyl group,
an optionally-substituted C.sub.1-6 alkoxy group, an
optionally-substituted C.sub.1-4 haloalkyl group, an
optionally-substituted C.sub.1-4 haloalkoxy group, cyano group,
nitro group, an optionally-substituted aryl group, an
optionally-substituted heteroaryl group, and an
optionally-substituted amino group; more preferably hydrogen atom,
halogen atom, an optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.1-6 alkoxy group, an
optionally-substituted C.sub.1-4 haloalkyl group, and an
optionally-substituted C.sub.1-4 haloalkoxy group; and even more
preferably hydrogen atom, halogen atom, and an
optionally-substituted C.sub.1-6 alkyl group.
[0210] The "R.sup.8' and R.sup.9'" used herein independently
include preferably hydrogen atom, an optionally-substituted
C.sub.1-6 alkyl group, an optionally-substituted C.sub.3-8
cycloalkyl group, an optionally-substituted C.sub.5-8 cycloalkenyl
group, an optionally-substituted aryl group, and an
optionally-substituted heteroaryl group; and more preferably an
optionally-substituted C.sub.1-6 alkyl group and an
optionally-substituted C.sub.3-8 cycloalkyl group.
[0211] The "R.sup.10, R.sup.10', R.sup.11 and R.sup.11'" used
herein independently include preferably hydrogen atom, halogen
atom, hydroxy group, an optionally-substituted C.sub.1-6 alkyl
group, and an optionally-substituted C.sub.1-6 alkoxy group; and
more preferably hydrogen atom, an optionally-substituted C.sub.1-6
alkyl group, and an optionally-substituted C.sub.1-6 alkoxy
group.
[0212] The "l" used herein includes an integer of preferably 0 and
1.
[0213] The "m" used herein includes an integer of preferably 0 and
1.
[0214] The "n" used herein includes an integer of preferably 0 and
1.
[0215] The "o" used herein includes an integer of preferably 0 and
1.
[0216] The "q" used herein includes an integer of preferably 1 to
3.
[0217] The "r and r'" used herein independently include an integer
of preferably 1 to 2.
[0218] The "s and s'" used herein independently include an integer
of preferably 0 and 1.
[0219] The "t and t'" used herein independently include an integer
of preferably 1.
[0220] The "u" used herein includes an integer of preferably 0 to
2, and more preferably 0 and 1.
[0221] The "v" used herein includes an integer of preferably 1 and
2.
[0222] The "Formulae (A-1) to (A-4)" used herein may be
independently and optionally substituted with one or more
substituents independently-selected from the group consisting of
preferably C.sub.1-6 alkyl group, hydroxy group, and C.sub.1-6
alkoxy group at each substitutable position thereof.
[0223] In case that R.sup.8, R.sup.9 and D are independently
C.sub.1-6 alkyl group, C.sub.3-6 alkenyl group, C.sub.3-6 alkynyl
group, C.sub.3-8 monocyclic, C.sub.7-10 bicyclic or C.sub.7-12
tricyclic cycloalkyl group, or C.sub.5-8 monocyclic or C.sub.7-10
bicyclic cycloalkenyl group; the R.sup.8, R.sup.9 and D may be
independently and optionally substituted with one or more
substituents independently-selected from the group consisting of
preferably alkyl group, hydroxy group, C.sub.1-4 alkoxy group,
C.sub.1-4 haloalkyl group, and aryl group at each substitutable
position thereof.
[0224] In case that R.sup.8, R.sup.9 and D are independently
--(CH.sub.2).sub.u--R.sup.12 wherein u is an integer of 1 to 4; the
alkylene chain may be optionally substituted with one or more
substituents independently-selected from the group consisting of
preferably C.sub.1-6 alkyl group, hydroxy group, and C.sub.1-6
alkoxy group at each substitutable position thereof.
[0225] In case that R.sup.13 is C.sub.1-6 alkyl group, C.sub.3-6
alkenyl group, C.sub.3-6 alkynyl group, C.sub.3-8 cycloalkyl group,
or C.sub.5-8 cycloalkenyl group; the R.sup.13 may be independently
and optionally substituted with one or more substituents
independently-selected from the group consisting of preferably
C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy group,
C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy group, and halogen
atom at each substitutable position thereof.
[0226] In case that R.sup.16 is C.sub.1-6 alkyl group, C.sub.3-6
alkenyl group, C.sub.3-6 alkynyl group, C.sub.3-8 cycloalkyl group,
C.sub.5-8 cycloalkenyl group, 5- to 9-membered monocyclic or 7- to
10-membered bicyclic non-aromatic unsaturated heterocyclic group,
or 4- to 9-membered monocyclic or 7- to 10-membered bicyclic
saturated heterocyclic group; the R.sup.16 may be independently and
optionally substituted with one or more substituents
independently-selected from the group consisting of preferably
C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy group,
C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy group, oxo group,
aryl group, heteroaryl group, and halogen atom; and more preferably
C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy group,
C.sub.1-4 haloalkyl group, and C.sub.1-4 haloalkoxy group at each
substitutable position thereof.
[0227] In case that R.sup.16 is aryl group or heteroaryl group; the
R.sup.16 may be independently and optionally substituted with one
or more substituents independently-selected from the group
consisting of preferably halogen atom, hydroxy group, C.sub.1-4
alkyl group, C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl group,
C.sub.1-4 haloalkoxy group, cyano group, and an
optionally-substituted amino group; more preferably, halogen atom,
C.sub.1-4 alkyl group, C.sub.1-4 alkoxy group, C.sub.1-4 haloalkyl
group, C.sub.1-4 haloalkoxy group, and an optionally-substituted
amino group; and even more preferably halogen atom, C.sub.1-4 alkyl
group, C.sub.1-4 alkoxy group, and an optionally-substituted amino
group at each substitutable position thereof.
[0228] In case that R.sup.19 and R.sup.20 are taken together with
the adjacent nitrogen atom to form a saturated or unsaturated 4- to
8-membered monocyclic nitrogen-containing heterocyclic group
comprising additional 0 to 2 heteroatoms independently-selected
from the group consisting of 1 to 2 nitrogen atoms, 1 oxygen atom
and 1 sulfur atom; the formed ring may be optionally substituted
with one or more substituents independently-selected from the group
consisting of preferably C.sub.1-4 alkyl group, hydroxy group,
alkoxy group, oxo group and halogen atom at each substitutable
position thereof.
[0229] In case that R.sup.14 and R.sup.15 are independently
C.sub.1-6 alkyl group, C.sub.3-6 alkenyl group, C.sub.3-6 alkynyl
group, C.sub.3-8 cycloalkyl group, C.sub.5-8 cycloalkenyl group, 5-
to 9-membered monocyclic or 7- to 10-membered bicyclic non-aromatic
unsaturated heterocyclic group, 4- to 9-membered monocyclic or 7-
to 10-membered bicyclic saturated heterocyclic group, C.sub.2-6
alkanoyl group, C.sub.1-6 alkoxycarbonyl group, or C.sub.1-6
alkylsulfonyl group; the R.sup.14 and R.sup.15 may be independently
and optionally substituted with one or more substituents
independently-selected from the group consisting of preferably
C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy group, oxo
group, aryl group, heteroaryl group, and halogen atom; and more
preferably C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy
group, and halogen atom at each substitutable position thereof.
[0230] In case that R.sup.14 and R.sup.15 are taken together with
the adjacent nitrogen atom to form a saturated or unsaturated 4- to
9-membered monocyclic or 7- to 10-membered bicyclic
nitrogen-containing heterocyclic group comprising additional 0 to 2
heteroatoms independently-selected from the group consisting of 1
to 2 nitrogen atoms, 1 oxygen atom and 1 sulfur atom; the formed
ring may be optionally substituted with one or more substituents
independently-selected from the group consisting of preferably
C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy group,
C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy group, oxo group,
and halogen atom; and more preferably, C.sub.1-4 alkyl group,
hydroxy group, C.sub.1-4 alkoxy group, oxo group, and halogen atom
at each substitutable position thereof.
[0231] In case that R.sup.8' and R.sup.9' are independently
C.sub.1-6 alkyl group, C.sub.3-6 alkenyl group, C.sub.3-6 alkynyl
group, C.sub.3-6 cycloalkyl group, C.sub.5-6 cycloalkenyl group, 5-
to 9-membered monocyclic or 7- to 10-membered bicyclic non-aromatic
unsaturated heterocyclic group, or 4- to 9-membered monocyclic or
7- to 10-membered bicyclic saturated heterocyclic group; the
R.sup.8' and R.sup.9' may be independently and optionally
substituted with one or more substituents independently-selected
from the group consisting of preferably C.sub.1-4 alkyl group,
hydroxy group, C.sub.1-4 alkoxy group, C.sub.1-4 haloalkoxy group,
oxo group, aryl group, heteroaryl group, aryloxy group, and halogen
atom; and more preferably C.sub.1-4 alkyl group, hydroxy group,
C.sub.1-4 alkoxy group, oxo group, and halogen atom at each
substitutable position thereof.
[0232] In case that a pair of R.sup.8 and R.sup.9, and a pair of
R.sup.8' and R.sup.9' are independently taken together with the
adjacent nitrogen atom to form a saturated or unsaturated 4- to
9-membered monocyclic or 7- to 10-membered bicyclic
nitrogen-containing heterocyclic group comprising additional 0 to 2
heteroatoms independently-selected from the group consisting of 1
to 2 nitrogen atoms, 1 oxygen atom and 1 sulfur atom; the formed
rings may be independently and optionally substituted with one or
more substituents independently-selected from the group consisting
of preferably C.sub.1-4 alkyl group, and oxo group at each
substitutable position thereof.
[0233] In case that R.sup.10, R.sup.10', R.sup.11 and R.sup.11' are
independently C.sub.1-6 alkyl group, C.sub.2-6 alkenyl group,
C.sub.2-6 alkynyl group, or C.sub.1-6 alkoxy group; the R.sup.10,
R.sup.10', R.sup.11 and R.sup.11' may be independently and
optionally substituted with one or more substituents
independently-selected from the group consisting of preferably
C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy group,
C.sub.1-4 haloalkoxy group, oxo group, aryl group, heteroaryl
group, aryloxy group, and halogen atom; and more preferably,
C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy group, and
halogen atom at each substitutable position thereof.
[0234] In case that a pair of R.sup.10 and R.sup.11, and a pair of
R.sup.10' and R.sup.11' are independently taken together to form an
optionally-substituted saturated or unsaturated 3- to 8-membered
ring that may comprise 1 oxygen atom, which may be a bicyclic or a
spiro compound with the ring to which the pair of R.sup.10 and
R.sup.11, or R.sup.10' and R.sup.11' is attached; the formed rings
may be independently and optionally substituted with one or more
substituents independently-selected from the group consisting of
preferably C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy
group, oxo group, and halogen atom at each substitutable position
thereof.
[0235] In case that R.sup.1 is C.sub.1-6 alkyl group, C.sub.2-6
alkenyl group, C.sub.2-6 alkynyl group, C.sub.3-8 cycloalkyl group,
or C.sub.5-8 cycloalkenyl group; the R.sup.1 may be independently
and optionally substituted with one or more substituents
independently-selected from the group consisting of preferably
C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy group,
C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy group, and halogen
atom; and more preferably C.sub.1-4 alkyl group, hydroxy group, and
C.sub.1-4 alkoxy group at each substitutable position thereof.
[0236] In case that R.sup.2 is C.sub.1-6 alkyl group, C.sub.2-6
alkenyl group, C.sub.2-6 alkynyl group, C.sub.3-8 cycloalkyl group,
C.sub.5-8 cycloalkenyl group, C.sub.1-6 alkoxy group, C.sub.1-4
haloalkyl group, or C.sub.1-4 haloalkoxy group; the R.sup.2 may be
independently and optionally substituted with one or more
substituents independently-selected from the group consisting of
preferably C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy
group, C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy group, and
halogen atom; and more preferably C.sub.1-4 alkyl group, hydroxy
group, and C.sub.1-4 alkoxy group at each substitutable position
thereof.
[0237] In case that R.sup.3 is C.sub.1-6 alkyl group, C.sub.2-6
alkenyl group, C.sub.2-6 alkynyl group, C.sub.3-8 cycloalkyl group,
C.sub.5-8 cycloalkenyl group, C.sub.1-6 alkoxy group, C.sub.1-4
haloalkyl group, haloalkoxy group, 5- to 9-membered monocyclic or
7- to 10-membered bicyclic non-aromatic unsaturated heterocyclic
group, or 4- to 9-membered monocyclic or 7- to 10-membered bicyclic
saturated heterocyclic group; the R.sup.3 may be independently and
optionally substituted with one or more substituents
independently-selected from the group consisting of preferably
C.sub.1-4 alkyl group, hydroxy group, alkoxy group, C.sub.1-4
haloalkyl group, C.sub.1-4 haloalkoxy group, and halogen atom; and
more preferably C.sub.1-4 alkyl group, hydroxy group, and C.sub.1-4
alkoxy group at each substitutable position thereof.
[0238] In case that R.sup.4 is C.sub.1-6 alkyl group, C.sub.2-6
alkenyl group, C.sub.2-6 alkynyl group, C.sub.3-8 cycloalkyl group,
C.sub.5-8 cycloalkenyl group, C.sub.1-6 alkoxy group, C.sub.1-4
haloalkyl group, or C.sub.1-4 haloalkoxy group; the R.sup.4 may be
independently and optionally substituted with one or more
substituents independently-selected from the group consisting of
preferably C.sub.1-4 alkyl group, hydroxy group, C.sub.1-4 alkoxy
group, C.sub.1-4 haloalkyl group, C.sub.1-4 haloalkoxy group, and
halogen atom; and more preferably C.sub.1-4 alkyl group, hydroxy
group, and C.sub.1-4 alkoxy group at each substitutable position
thereof.
[0239] In case that R.sup.3 and R.sup.4 are taken together to form
a saturated or unsaturated 6- to 9-membered ring optionally
comprising 1 oxygen atom; the formed ring may be optionally
substituted with one or more substituents independently-selected
from the group consisting of preferably C.sub.1-4 alkyl group,
hydroxy group, alkoxy group, oxo group, and halogen atom at each
substitutable position thereof.
[0240] In case that R.sup.5 and R.sup.6 are independently C.sub.1-6
alkyl group, C.sub.2-6 alkenyl group, C.sub.2-6 alkynyl group,
C.sub.3-8 cycloalkyl group, C.sub.5-8 cycloalkenyl group, C.sub.1-6
alkoxy group, C.sub.1-4 haloalkyl group, or C.sub.1-4 haloalkoxy
group; the R.sup.5 and R.sup.6 may be independently and optionally
substituted with one or more substituents independently-selected
from the group consisting of preferably C.sub.1-4 alkyl group,
hydroxy group, alkoxy group, C.sub.1-4 haloalkyl group, C.sub.1-4
haloalkoxy group, and halogen atom; and more preferably C.sub.1-4
alkyl group, hydroxy group, and C.sub.1-4 alkoxy group at each
substitutable position thereof.
[0241] Hereinafter, the compound of Formula (1) in the present
invention is explained in more detail.
[0242] The compound of Formula (1) may encompass all tautomers,
geometric isomers, stereoisomers and a mixture thereof depending on
the types of substituents.
[0243] To be more specific, the compound of Formula (1) with one or
more chiral carbon atoms exists in the form of a diastereomer or
optical isomer, and the present invention encompasses a mixture or
an isolated one of the diastereomer or optical isomer.
[0244] The present invention also includes an isotope-labeled
compound of Formula (1) and a pharmaceutically acceptable salt
thereof, wherein the isotope-labeled compound is the same as the
compound of Formula (1) except that one or more atoms in the
compound have an atomic mass or a mass number which is different
from the typical atomic mass or mass number present in nature. The
present compound includes an isotope of, for example, hydrogen,
carbon, nitrogen, oxygen, phosphorus, fluorine, bromine, and
chlorine. In specific, the present compound includes isotopes such
as .sup.2H, .sup.3H, .sup.11C, .sup.13C, .sup.14C, .sup.13N,
.sup.15N, .sup.18O, .sup.17O, .sup.15O, .sup.18F, .sup.75Br,
.sup.76Br, .sup.77Br, .sup.82 Br, and .sup.36Cl. The present
invention also includes the present compounds which comprise the
above-mentioned isotopes and/or other isotopes of other atoms, and
pharmaceutically acceptable salts thereof.
[0245] A particular isotope-labeled compound of the present
invention (e.g. a compound comprising radioisotopes such as
.sup.11C, .sup.3H and .sup.18F) is useful, for example, in a tissue
distribution assay of the medicament and/or substrate, and
especially useful as a diagnostic agent to find out the
localization of the 5-HT.sub.4 receptor subtype which is a
serotonin receptor. The isotopes of tritium (i. .sup.3H), carbon-11
(i.e. .sup.11C), and .sup.18F are especially preferable because
they can be easily manufactured and detected. Thus, these compounds
are also useful to assess the density of the said receptor in each
region of the central nervous system, and to assess the receptor
occupancy obtained by using a certain concentration of these
compounds. The results of the assessment are likely to be helpful
in determining the dosage and dose of these compounds. Furthermore,
from this viewpoint, these isotope-labeled compounds can also be
used for studying the characteristics of diseases which could have
not been diagnosed in the past.
[0246] In addition, the substitution with heavy isotopes such as
deuterium, i.e. .sup.2H can provide some therapeutic benefits owing
to increased metabolic stability (such as prolongation of in vivo
half-life and decrease of the required dosage), and thus the
compound having heavy isotopes may be preferable in some
situations.
[0247] The pharmaceutically acceptable salt used herein includes an
acid addition salt and a base addition salt. For example, the acid
addition salt includes an inorganic acid salt such as
hydrochloride, hydrobromide, sulfate, hydrogen sulfate,
hydroiodide, nitrate, and phosphate; and an organic acid salt such
as citrate, oxalate, acetate, formate, propionate, benzoate,
trifluoroacetate, fumarate, maleate, malonate, succinate, tartrate,
hydrogen tartrate, lactate, malate, pyruvate, gluconate,
saccharate, methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate, and pamoate [i.e.
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)]. The base addition
salt includes an inorganic base salt such as sodium salt, potassium
salt, calcium salt, magnesium salt, and ammonium salt; and an
organic base salt such as triethylammonium salt, triethanolammonium
salt, pyridinium salt, and diisopropylammonium salt. The
pharmaceutically acceptable salt may also include a basic amino
acid salt such as alginate, aspartate, and glutamate; and an acidic
amino acid salt. The salt used herein includes preferably
hydrochloride, hydrobromide, sulfate, phosphate, citrate, fumarate,
maleate, malonate, succinate, tartrate, lactate, malate, pyruvate,
methanesulfonate, and benzenesulfonate.
[0248] The compound of Formula (1) and a pharmaceutically
acceptable salt thereof may be a solvate such as a hydrate or an
ethanolate, and the hydrate and/or solvate are also included in the
present compound.
Process of the Present Compound
[0249] Hereinafter, several processes of the present compound of
Formula (1):
##STR00018##
are explained with examples, but the present invention should not
be limited thereto. The compound of Formula (1) can be synthesized
from a well-known compound by combining several well-known
processes. For example, the compound can be prepared as
follows.
(Process 1)
[0250] The compound of Formula (1) in which, for example, D is
(CH.sub.2).sub.u--(R.sup.12-1) [i.e. Compound (1')] can be prepared
by the following process:
##STR00019##
wherein r', s', u, A, B, U, V, W, X, Y, Z, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.10, R.sup.11' and R.sup.13 are as defined
above, and L.sup.1 is a leaving group.
[0251] In specific, the compound of Formula (1') can be prepared by
reacting the compound of Formula (1-1) with the reactive derivative
of Formula (1-2) in the presence of an appropriate additive such as
a base.
[0252] In case that --R.sup.13 is --COR.sup.16 wherein R.sup.16 is
as defined above, the reactive derivative of Formula (1-2) wherein
L.sup.1 is hydroxy group may include the carboxylic acid compound
of Formula (1-3):
[0253] R.sup.16--COOH wherein R.sup.16 is as defined above, and an
alkyl ester thereof (in particular, a methyl ester), an active
ester thereof, an acid anhydride thereof, and a carboxylic halide
thereof (in particular, a carboxylic chloride).
[0254] The carboxylic acid compound of Formula (1-3) may be reacted
in the presence of a condensing agent such as
1,3-dicyclohexylcarbodiimide,
1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride,
N,N'-carbonyldiimidazole,
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexa-fluorophosphate, N,N'-carbonyldisuccinimide,
1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, diphenylphosphoryl
azide, and propanephosphonic anhydride. In case that
1,3-dicyclohexylcarbodiimide or
1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride is
used as the condensing agent, N-hydroxysuccinimide,
1-hydroxybenzotriazole, 3-hydroxy-1,2,3-benzotriazin-4(3H)-one,
N-hydroxy-5-norbornene-2,3-dicarboxylmide, etc. may be added to the
reaction.
[0255] The active ester of the carboxylic acid compound of Formula
(1-3) specifically includes p-nitrophenyl ester, pentachlorophenyl
ester, pentafluorophenyl ester, N-hydroxysuccinimide ester,
N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester,
8-hydroxyquinoline ester, 2-hydroxyphenyl ester, etc.
[0256] The acid anhydride of carboxylic acid compound of Formula
(1-3) used herein may include a symmetrical acid anhydride or a
mixed acid anhydride; and the mixed acid anhydride specifically
includes a mixed acid anhydride with an alkyl chlorocarbonate such
as ethyl chlorocarbonate and isobutyl chlorocarbonate, a mixed acid
anhydride with an aralkyl chlorocarbonate such as benzyl
chlorocarbonate, a mixed acid anhydride with an aryl
chlorocarbonate such as phenyl chlorocarbonate, and a mixed acid
anhydride with an alkanoic acid such as isovaleric acid and pivalic
acid.
[0257] In case that --R.sup.13 of Formula (1') is --COOR.sup.16
wherein R.sup.16 is as defined above, the reactive derivative of
Formula (1-2) may include the compound of Formula (1-4):
[0258] R.sup.16O--CO-L.sup.1 wherein L.sup.1 and R.sup.16 are
defined as above. The compound of Formula (1-4) wherein L.sup.1 is
chlorine atom is commercially available, or can be prepared by
reacting R.sup.16OH and phosgene, diphosgene or a phosgene
equivalent such as triphosgene.
[0259] In case that --R.sup.13 of Formula (1') is
--SO.sub.2--R.sup.16 wherein R.sup.16 is as defined above, the
reactive derivative of Formula (1-2) may include the compound of
Formula (1-5):
[0260] R.sup.16--SO.sub.2-L.sup.1 wherein L.sup.1 and R.sup.16 are
defined as above.
[0261] In case that --R.sup.13 of Formula (1') is
--CONR.sup.19R.sup.20 wherein R.sup.19 and R.sup.20 are as defined
above, the reactive derivative of Formula (1-2) may include the
compound of Formula (1-6):
[0262] R.sup.19R.sup.20N--CO-L.sup.1 wherein L.sup.1, R.sup.19 and
R.sup.20 are defined as above.
[0263] The reaction of the compound of Formula (1-1) and the
reactive derivative of Formula (1-2) can be carried out in the
presence or absence of a solvent. The solvent used herein should be
optionally selected depending on the types of starting compounds
and other factors, and includes, for example, aromatic hydrocarbons
such as benzene, toluene, and xylene; ethers such as diethyl ether,
tetrahydrofuran, dioxane, cyclopentyl methyl ether; halogenated
hydrocarbons such as methylene chloride and chloroform; ketones
such as acetone and methyl ethyl ketone; ethyl acetate;
acetonitrile; N,N-dimethylformamide; and dimethylsulfoxide. These
solvents may be used alone or in a mixture of two or more.
[0264] The reaction may be optionally carried out in the presence
of a base. The base used herein includes specifically alkali
hydroxides such as sodium hydroxide and potassium hydroxide;
alkaline carbonates such as sodium carbonate and potassium
carbonate; alkaline bicarbonates such as sodium bicarbonate and
potassium bicarbonate; and organic bases such as triethylamine,
tributylamine, diisopropylethylamine, and N-methylmorpholine. In
order to also use the compound of Formula (1-1) as a base, an
excess amount of the compound may be used.
[0265] The reaction temperature depends on the types of the
starting compound used herein or other factors; and it is typically
about -30.degree. C. to about 200.degree. C., and preferably about
-10.degree. C. to about 150.degree. C.
[0266] The leaving group of L.sup.1 used herein includes, for
example, halogen atoms such as chlorine, bromine, and iodine;
alkylsulfonyloxy groups such as methanesulfonyloxy group; and
arylsulfonyloxy groups such as benzenesulfonyloxy group and
p-toluenesulfonyloxy group; and preferably halogen atoms (in
particular, chlorine and bromine), methanesulfonyloxy, and
p-toluenesulfonyloxy.
[0267] The compound of Formula (1-1) described in Process 1 in
which, for example, B is (B-2), D is
(CH.sub.2).sub.u--(R.sup.12-1), and u is 1 [i.e. Compound (1-1')]
can be prepared by the following Process 2.
[0268] Furthermore, in case that B is (B-2), D is
(CH.sub.2).sub.u--(R.sup.12-1), and u is 0 [i.e. Compound (1-1'')],
the compound can be prepared by the following Process 3.
(Process 2)
##STR00020##
[0269] wherein
[0270] r, s, r', s', A, U, V, W, X, Y, Z, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.16, R.sup.11, R.sup.10' and R.sup.11' are
as defined above,
[0271] L.sup.2 is a protecting group which may be eliminated by
hydrolysis or hydrogenolysis, and
[0272] L.sup.3 is --CH.sub.2-L.sup.4 (wherein L.sup.4 is a leaving
group) or formyl group.
(Process 3)
##STR00021##
[0273] wherein
[0274] r, s, r', s', A, U, V, W, X, Y, Z, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.10, R.sup.11, R.sup.10' and R.sup.11' are
as defined above,
[0275] L.sup.2 is a protecting group which may be eliminated by
hydrolysis or hydrogenolysis, and
[0276] L.sup.5 is oxo group or a leaving group.
[0277] Hereinafter, Steps 1 to 4 of the above Processes 2 and 3 are
explained.
1) Alkylation step by substitution reaction (Step 1, Step 3)
[0278] When L.sup.3 is --CH.sub.2-L.sup.4 (wherein L.sup.4 is a
leaving group) in the compound of Formula (2-2) which is an
intermediate of Process 2 and when L.sup.5 is a leaving group in
the compound of Formula (3-1) which is an intermediate of Process
3, Step 1 and Step 3 are an alkylation step carried out by a
substitution reaction in the presence or absence of a solvent. The
solvent used herein should be optionally selected depending on the
types of starting compounds, etc., and includes for example,
aromatic hydrocarbons such as benzene, toluene, and xylene; ethers
such as diethyl ether, tetrahydrofuran, cyclopentyl methyl ether,
and dioxane; halogenated hydrocarbons such as methylene chloride
and chloroform; alcohols such as ethanol, isopropanol, and ethylene
glycol; ketones such as acetone and methyl ethyl ketone; ethyl
acetate, acetonitrile; N,N-dimethylformamide; and
dimethylsulfoxide. These solvents may be used alone or in a mixture
of two or more.
[0279] The reaction can be carried out in the presence of a base as
appropriate, and the base used herein includes alkali hydroxides
such as sodium hydroxide and potassium hydroxide; alkaline
carbonates such as sodium carbonate and potassium carbonate;
alkaline bicarbonates such as sodium bicarbonate and potassium
bicarbonate; and organic bases such as triethylamine,
tributylamine, diisopropylethylamine, and N-methylmorpholine. In
order to also use the compound of Formula (2-1) as a base, an
excess amount of the compound may be used.
[0280] The leaving groups of L.sup.4 and L.sup.5 include, for
example, halogen atoms such as chlorine, bromine, and iodine;
alkylsulfonyloxy groups such as methanesulfonyloxy group; and
arylsulfonyloxy groups such as benzenesulfonyloxy group and
p-toluenesulfonyloxy group; and preferably halogen atoms (in
particular, chlorine and bromine), methanesulfonyloxy, and
p-toluenesulfonyloxy. In case that L.sup.4 and L.sup.5 are chlorine
or bromine, the reaction smoothly proceeds by adding alkali metal
iodides such as sodium iodide and potassium iodide.
[0281] The reaction temperature depends on the types of the
starting compound used herein or other factors; and it is typically
about 0.degree. C. to about 200.degree. C., preferably about
20.degree. C. to about 150.degree. C.
[0282] The compounds of Formula (2-2) and Formula (3-1) are
commercially available, or may be prepared according to known
methods. In specific, the compounds of Formula (2-2) and Formula
(3-1) wherein L.sup.4 and L.sup.5 are a leaving group can be
prepared from the corresponding alcohol derivatives of Formula
(2-2a) and Formula (3-1a) by converting the corresponding group
into a leaving group according to conventional methods:
##STR00022##
wherein r', s', R.sup.10', R.sup.11' and L.sup.2 are as defined
above; and L.sup.4 and L.sup.5 are a leaving group.
[0283] For example, the compound of Formula (2-2a) can be reacted
with carbon tetrachloride or carbon tetrabromide and
triphenylphosphine to give a compound wherein L.sup.4 is chlorine
atom or bromine atom. Alternatively, the compound of Formula (2-2a)
can be reacted with sulfonyl chloride compounds such as
benzenesulfonyl chloride in the presence of a base to give a
compound wherein L.sup.4 is arylsulfonyloxy group or
alkylsulfonyloxy group.
2) Reductive Alkylation Step (Step 1, Step 3)
[0284] When L.sup.3 is formyl group in the compound of Formula
(2-2) which is an intermediate of Process 2 and when L.sup.5 is oxo
group in the compound of Formula (3-1) which is an intermediate of
Process 3, Step 1 and Step 3 are a reductive alkylation step and
can be, for example, carried out under the following
conditions:
1. a catalytic reduction using platinum oxide or palladium carbon
as a catalyst in the presence of, if necessary, a catalytic amount
of acid 2. a reduction using borane complex such as pyridine borane
and triethylamine borane, sodium borohydride, sodium
triacetoxyhydroborate, or sodium cyanoborohydride in the presence
of, if necessary, a catalytic or excess amount of acid. The solvent
used herein includes the solvents mentioned in the above-mentioned
1). The acid used herein includes, for example, p-toluenesulfonic
acid, hydrogen chloride, and titanium tetraisopropoxide. The
reaction temperature is usually about 0.degree. C. to about
100.degree. C., and preferably about 20.degree. C. to about
80.degree. C.
[0285] The compounds of Formula (2-2) and Formula (3-1) used herein
are commercially available, or may be prepared according to known
methods. In specific, the compounds of Formula (2-2) wherein
L.sup.3 is formyl group and Formula (3-1) wherein L.sup.5 is oxo
group can be prepared by oxidizing the corresponding alcohol
derivatives of Formula (2-2) and Formula (3-1a) according to
conventional methods. For example, the compounds of Formula (2-2a)
and Formula (3-1a) can be oxidized with phosgene, dimethylsulfoxide
and triethylamine.
[0286] Alternatively, the compound of Formula (2-2) can also be
prepared by reducing the corresponding carboxylic acid or an ester
thereof according to conventional methods, and for example, by
reducing the compound of Formula (2-2b) with DIBAH (i.e.
diisobutylaluminium hydride).
##STR00023##
wherein r', s', R.sup.10', R.sup.11' and L.sup.2 are as defined
above.
[0287] In addition, the compound of Formula (2-2b) used herein is
commercially available, or may be prepared according to known
methods.
3) Deprotection Step (Step 2, Step 4)
[0288] Step 2 and Step 4 are a deprotection reaction. Among the
protecting groups of L.sup.2 used in Processes 2 and 3, protecting
groups which may be eliminated by hydrolysis include, for example,
ethoxycarbonyl group, tert-butoxycarbonyl group, acetyl group,
benzoyl group, trifluoroacetyl group, benzyloxycarbonyl group, 3-
or 4-chlorobenzyloxycarbonyl group, triphenylmethyl group,
methanesulfonyl group, and p-toluenesulfonyl group.
[0289] The deprotection by hydrolysis can be carried out according
to conventional methods, and for example, it may be carried out by
contacting the protecting group with water in a suitable solvent
under an acidic or basic condition. The solvent used herein
includes, for example, alcohols such as methanol, ethanol, and
isopropanol; acetonitrile; dioxane; water; and a mixture thereof.
The acid used herein specifically includes mineral acids such as
hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfuric
acid; and organic acids such as formic acid, acetic acid,
trifluoroacetic acid, p-toluenesulfonic acid, and methanesulfonic
acid. The base used herein specifically includes alkali hydroxides
such as sodium hydroxide and potassium hydroxide; and alkaline
carbonates such as sodium carbonate and potassium carbonate. The
reaction temperature is usually about 0.degree. C. to about
150.degree. C.
[0290] Among the protecting groups of L.sup.2, protecting groups
which may be eliminated by hydrogenolysis include, for example,
benzyloxycarbonyl group, 3- or 4-chlorobenzyloxycarbonyl group,
benzyl group, and 4-methoxybenzyl group. The deprotection by
hydrogenolysis can be carried out according to conventional
methods, and for example, it may be carried out by reacting the
protecting group in a suitable solvent in the presence of a
catalyst (such as palladium carbon and Raney nickel), and in the
presence of hydrogen or a hydrogen donor (such as ammonium formate
and cyclohexene). The solvent used herein includes, for example,
alcohols such as ethanol and methanol, water, acetic acid, dioxane,
tetrahydrofuran, ethyl acetate, and N,N-dimethylformamide. The
reaction is carried out at a temperature of usually about 0.degree.
C. to about 80.degree. C., under normal or high pressure.
[0291] The compound of Formula (2-1) described in Processes 2 and 3
can be prepared by the methods of the following Processes 4 to
6.
(Process 4)
[0292] The compound of Formula (2-1') wherein, for example, X is
nitrogen atom, Z is nitrogen atom, Y is oxygen atom, U is carbon
atom, A is Formula (A-1), and B is Formula (B-2) can be prepared by
the following process:
##STR00024##
wherein l, r, s, V, W, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.10, R.sup.11 and L.sup.2 are as defined above, L.sup.6 is a
leaving group, and L.sup.7 is hydroxy group or a leaving group.
[0293] Step 1 is a cyanation step. The leaving group of L.sup.6
used herein includes, for example, bromine and p-toluenesulfonyl
group. The base used herein is one or a mixture of two or more
bases selected from the group consisting of, for example,
trimethylamine, triethylamine, DMAP (i.e.
4-N,N-dimethylaminopyridine), pyridine, potassium tert-butoxide,
butyllithium, sodium hydride, lithium hexamethyldisilazide, and
cesium carbonate. The reaction temperature is usually about
-80.degree. C. to about 100.degree. C., and preferably about
0.degree. C. to about 80.degree. C. The solvent used herein
includes, for example, aromatic hydrocarbons such as benzene,
toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran,
cyclopentyl methyl ether and dioxane; halogenated hydrocarbons such
as methylene chloride and chloroform; alcohols such as ethanol,
isopropanol, and ethylene glycol; ketones such as acetone and
methyl ethyl ketone; ethyl acetate; acetonitrile;
N,N-dimethylformamide; and dimethylsulfoxide. These solvents may be
used alone or in a mixture of two or more.
[0294] Step 2 is a reaction to obtain an amidinoxime compound by
reacting cyano group with hydroxylamine. The reaction can be
carried out in the presence of a base as appropriate, and the base
specifically includes alkali hydroxides such as sodium hydroxide
and potassium hydroxide; alkaline carbonates such as sodium
carbonate and potassium carbonate; alkaline bicarbonates such as
sodium bicarbonate and potassium bicarbonate; and organic bases
such as triethylamine, tributylamine, diisopropylethylamine, and
N-methylmorpholine. The solvent used herein includes, for example,
aromatic hydrocarbons such as benzene, toluene, and xylene; ethers
such as diethyl ether, tetrahydrofuran, cyclopentyl methyl ether,
and dioxane; halogenated hydrocarbons such as methylene chloride
and chloroform; alcohols such as ethanol, isopropanol, and ethylene
glycol; ketones such as acetone and methyl ethyl ketone; ethyl
acetate; acetonitrile; N,N-dimethylformamide; dimethylsulfoxide;
and water. These solvents may be used alone or in a mixture of two
or more. The reaction temperature is usually about 0.degree. C. to
about 150.degree. C., and preferably 20.degree. C. to about
80.degree. C.
[0295] Step 3 is a condensation step (Step 3-1) followed by a
cyclization step (Step 3-2). In specific, the compound of Formula
(4-5) can be reacted with the reactive derivative of Formula (4-6)
in the presence of a suitable additive agent such as a base to give
the compound of Formula (4-7), and then the compound of Formula
(4-7) can be cyclized to give the compound of Formula (4-8).
Condensation Step (Step 3-1)
[0296] The reactive derivative of (4-6) includes a carboxylic acid
compound, and an alkyl ester thereof (in particular, methyl ester),
an active ester thereof, an acid anhydride thereof and an acid
halide thereof (including an acid derivative wherein the halide is
replaced with another leaving group which is a halide equivalent).
In case that the derivative (4-6) is a carboxylic acid compound
(i.e. L.sup.7 is hydroxy group), the reaction can be carried out in
the presence of a condensing agent such as
1,3-dicyclohexylcarbodiimide,
1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride,
N,N'-carbonyldiimidazole,
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexa-fluorophosphate, N,N'-carbonyldisuccinimide,
1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, diphenylphosphoryl
azide, and propanephosphonic anhydride. In addition, in case that
1,3-dicyclohexylcarbodiimide or
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride is used
as the condensing agent, N-hydroxysuccinimide,
1-hydroxybenzotriazole, 3-hydroxy-1,2,3-benzotriazin-4(3H)-one,
N-hydroxy-5-norbornene-2,3-dicarboxylmide, etc. may be added to the
reaction.
[0297] In case that the derivative (4-6) is an active ester, the
active ester specifically includes p-nitrophenyl ester,
pentachlorophenyl ester, pentafluorophenyl ester,
N-hydroxysuccinimide ester, N-hydroxyphthalimide ester,
1-hydroxybenzotriazole ester, 8-hydroxyquinoline ester,
2-hydroxyphenyl ester, etc.
[0298] In case that the derivative (4-6) is an acid anhydride, the
acid anhydride specifically includes a symmetrical acid anhydride
and a mixed acid anhydride. The mixed acid anhydride specifically
includes a mixed acid anhydride with an alkyl chlorocarbonate such
as ethyl chlorocarbonate and isobutyl chlorocarbonate, a mixed acid
anhydride with an aralkyl chlorocarbonate such as benzyl
chlorocarbonate, a mixed acid anhydride with an aryl
chlorocarbonate such as phenyl chlorocarbonate, and a mixed acid
anhydride with an alkanoic acid such as isovaleric acid and pivalic
acid.
[0299] The present reaction can be carried out in the presence or
absence of a solvent. The solvent used herein should be optionally
selected depending on the types of starting compounds, etc., and
for example, aromatic hydrocarbons such as benzene, toluene, and
xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, and
cyclopentyl methyl ether; halogenated hydrocarbons such as
methylene chloride and chloroform; ketones such as acetone and
methyl ethyl ketone; ethyl acetate; acetonitrile;
dimethylformamide; and dimethylsulfoxide. These solvents may be
used alone or in a mixture of two or more.
[0300] The reaction can be carried out in the presence of a base as
appropriate, and the base includes alkali hydroxides such as sodium
hydroxide and potassium hydroxide; alkaline carbonates such as
sodium carbonate and potassium carbonate; alkaline bicarbonates
such as sodium bicarbonate and potassium bicarbonate; and organic
bases such as triethylamine, tributylamine, diisopropylethylamine,
and N-methylmorpholine. In order to also use the compound of
Formula (4-5) as a base, an excess amount of the compound may be
used.
[0301] The reaction temperature depends on the types of the
starting compound used herein or other factors; and it is typically
about -30.degree. C. to about 200.degree. C., and preferably about
-10.degree. C. to about 150.degree. C.
[0302] In case that the derivative (4-6) is an acid halide
(including an acid derivative wherein the halide is replaced with
another leaving group which is a halide equivalent), L.sup.7
includes, for example, halogen atoms (such as chlorine, bromine,
and iodine) and detachable groups like halogen atoms (e.g.
alkylsulfonyloxy groups such as methanesulfonyloxy group, and
arylsulfonyloxy groups such as benzenesulfonyloxy group and
p-toluenesulfonyloxy group). L.sup.7 is preferably halogen atoms
(in particular, chlorine and bromine), methanesulfonyloxy group or
trifluoromethane-sulfonyloxy group.
[0303] The present reaction is carried out in the presence or
absence of a solvent. The solvent used herein should be optionally
selected depending on the types of starting compounds, etc., and
for example, aromatic hydrocarbons such as benzene, toluene, and
xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, and
cyclopentyl methyl ether; halogenated hydrocarbons such as
methylene chloride and chloroform; ketones such as acetone and
methyl ethyl ketone; ethyl acetate; acetonitrile;
N,N-dimethylformamide; and dimethylsulfoxide. These solvents may be
used alone or in a mixture of two or more.
[0304] The reaction can be carried out in the presence of a base as
appropriate, and the base includes alkali hydroxides such as sodium
hydroxide and potassium hydroxide; alkaline carbonates such as
sodium carbonate and potassium carbonate; alkaline bicarbonates
such as sodium bicarbonate and potassium bicarbonate; and organic
bases such as triethylamine, tributylamine, diisopropylethylamine,
and N-methylmorpholine. In order to also use the compound of
Formula (4-5) as a base, an excess amount of the compound may be
used.
[0305] The reaction temperature depends on the types of the
starting compound used herein or other factors; and it is typically
about 0.degree. C. to about 200.degree. C., and preferably about
20.degree. C. to about 150.degree. C.
Cyclization Step (Step 3-2)
[0306] According to the disclosure of, for example, Current Organic
Chemistry, (2008), 12(10), 850, the compound of Formula (4-7) can
be reacted in the presence or absence of a suitable additive agent
such as a base to give the compound of Formula (4-8).
[0307] The present reaction can be carried out in the presence or
absence of a solvent. The solvent used herein should be optionally
selected depending on the types of starting compounds, etc., and
includes, for example, aromatic hydrocarbons such as benzene,
toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran,
dioxane, and cyclopentyl methyl ether; halogenated hydrocarbons
such as methylene chloride and chloroform; ketones such as acetone
and methyl ethyl ketone; ethyl acetate; acetonitrile;
N,N-dimethylformamide; dimethylsulfoxide; and acetic acid. These
solvents may be used alone or in a mixture of two or more.
[0308] The base used herein includes, for example, alkaline
carbonates such as sodium carbonate and potassium carbonate;
alkaline bicarbonates such as sodium bicarbonate and potassium
bicarbonate; alkali acetates such as sodium acetate and potassium
acetate; and organic bases such as triethylamine, tributylamine,
diisopropylethylamine, methylmorpholine, tetrabutylammonium
fluoride, and quaternary ammonium hydroxide salts (e.g.
tetramethylammonium hydroxide). The reaction temperature depends on
the types of the starting compound used herein or other factors;
and it is typically about 0.degree. C. to about 200.degree. C.,
preferably about 20.degree. C. to about 110.degree. C.
[0309] Step 4 is a deprotection reaction. The compound of Formula
(4-8) can be deprotected in the same manner as in the
above-described L.sup.2 to give the compound of Formula (2-1').
(Process 5)
[0310] The compound of Formula (4-1) described in Process 4 is
commercially available, or may be prepared according to known
methods. The compound of Formula (4-1) wherein, for example, V is
nitrogen atom and W is carbon atom [i.e. the compound of (4-1')]
can be prepared by the following process:
##STR00025##
wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are as
defined above, X is a halogen atom (for example, when R.sup.3 is
methyl group, R.sup.3--MgX means methyl Grignard reagent).
[0311] Step 1 is an addition reaction of Grignard reagent to
nitrile group. In specific, the compound of Formula (5-1) can be
reacted with R.sup.3--MgX, and the resultant imine can be
hydrolyzed by an acid to give the compound of Formula (5-2).
[0312] The solvent used herein should be optionally selected
depending on the types of starting compounds, etc., and for
example, hydrocarbons such as hexane and n-heptane; aromatic
hydrocarbons such as benzene, toluene, and xylene; and ethers such
as diethyl ether, tetrahydrofuran, dioxane, and cyclopentyl methyl
ether. These solvents may be used alone or in a mixture of two or
more.
[0313] The acid used herein includes mineral acids such as
hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfuric
acid; and preferably hydrochloric acid. The reaction temperature is
usually about -80.degree. C. to about 120.degree. C., and
preferably about -40.degree. C. to about 60.degree. C.
[0314] In Step 2, the amino group of the compound of Formula (5-2)
can be diazotized in the presence of an acid, and the resultant
diazonium salt can be reduced to make an indazole ring to give the
compound of Formula (4-1').
[0315] The acid used herein includes, for example, hydrochloric
acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and
tetrafluoroboric acid; and preferably hydrochloric acid, sulfuric
acid, and tetrafluoroboric acid.
[0316] The diazotization agent used herein includes, for example,
nitrite salts such as sodium nitrite and potassium nitrite, and
nitrite esters such as pentyl nitrite and isoamyl nitrite; and
preferably sodium nitrite.
[0317] The reducing agent used herein includes, for example, tin
(II) chloride, sodium sulfite, sodium nitrite, sodium dithionite,
and sodium thiosulfate.
[0318] The reaction temperature is usually about -40.degree. C. to
about 80.degree. C., and preferably about -20.degree. C. to about
20.degree. C.
[0319] The solvent used herein includes the above-mentioned acids,
and additionally includes, for example, aromatic hydrocarbons such
as benzene, toluene, and xylene; ethers such as diethyl ether,
tetrahydrofuran, cyclopentyl methyl ether, and dioxane; halogenated
hydrocarbons such as methylene chloride and chloroform; alcohols
such as methanol, ethanol, isopropanol, and ethylene glycol; ethyl
acetate; acetonitrile; and water. These solvents may be used alone
or in a mixture of two or more.
[0320] Step 3 is Sugasawa reaction. The compound of Formula (5-3)
can be reacted with a nitrile derivative (defined as R.sup.3--CN)
in the presence of Lewis acid to give the compound of Formula
(5-2).
[0321] The Lewis acid used herein includes, for example, zinc
chloride, tin (IV) chloride, titanic chloride, aluminum chloride,
boron trichloride, and gallium trichloride. These Lewis acids may
be used alone or in a mixture of two or more. The Lewis acid used
herein is preferably a combination of boron trichloride and
aluminum chloride, or a combination of boron trichloride and
gallium trichloride.
[0322] The reaction temperature is usually about -20.degree. C. to
about 200.degree. C., preferably about -10.degree. C. to about
150.degree. C.
[0323] The solvent used herein includes, for example, aromatic
hydrocarbons such as benzene, toluene, and xylene; ethers such as
diethyl ether, tetrahydrofuran, cyclopentyl methyl ether and
dioxane; halogenated hydrocarbons such as methylene chloride,
chloroform, and 1,2-dichloroethane; ethyl acetate; acetonitrile;
and N,N-dimethylformamide. These solvents may be used alone or in a
mixture of two or more.
(Process 6)
[0324] The compound of Formula (1) can also be prepared by the
following process in case that, for example, B is Formula (B-2);
and D is an optionally-substituted C.sub.1-6 alkyl group, an
optionally-substituted C.sub.3-6 alkenyl group, an
optionally-substituted C.sub.3-6 alkynyl group, an
optionally-substituted C.sub.3-8 monocyclic, C.sub.7-10 bicyclic or
C.sub.7-12 tricyclic cycloalkyl group, or an
optionally-substituted. C.sub.5-8 monocyclic or C.sub.7-10 bicyclic
cycloalkenyl group [i.e. Compound (1'')]:
##STR00026##
wherein r, s, A, U, V, W, X, Y, Z, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.10 and R.sup.11 are as defined above, and L.sup.5 is
oxo group (provided that when L.sup.5 is attached to the primary
carbon atom of D, L.sup.5 forms a formyl group with the attached
carbon atom) or a leaving group.
[0325] In case that L.sup.5 is a leaving group, Step 1 is an
alkylation reaction. The compound of Formula (2-1) and the compound
of Formula (6-1) can be reacted in the same manner as in 1)
Alkylation step of Processes 2 and 3 to give the compound of
Formula (1'').
[0326] In case that L.sup.5 is oxo group, Step 1 is a reductive
alkylation reaction. The compound of Formula (2-1) and the compound
of Formula (6-1) can be reacted in the same manner as in 2)
Reductive alkylation step of Processes 2 and 3 to give the compound
of Formula (1'').
(Process 7)
[0327] The compound of Formula (1) can also be prepared by the
following process in case that, for example, B is Formula (B-2) and
D is Formula (R.sup.12-3) [i.e. Compound (1''')]:
##STR00027##
wherein r, s, r', s', u, A, U, V, W, X, Y, Z, R.sup.2, R.sup.4,
R.sup.5, R.sup.6, R.sup.10, R.sup.11, R.sup.10', and .sup.11' are
as defined above, and L.sup.5 is oxo group [provided that when
L.sup.5 is attached to the primary carbon atom in Formula (7-1),
L.sup.5 forms a formyl group with the attached carbon atom] or a
leaving group.
[0328] In case that L.sup.5 is a leaving group, Step 1 is an
alkylation reaction. The compound of Formula (2-1) and the compound
of Formula (7-1) can be reacted in the same manner as in 1)
Alkylation step of Processes 2 and 3 to give the compound of
Formula (1''').
[0329] In case that L.sup.5 is oxo group, Step 1 is a reductive
alkylation reaction. The compound of Formula (2-1) and the compound
of Formula (7-1) can be reacted in the same manner as in 2)
Reductive alkylation step of Processes 2 and 3 to give the compound
of Formula (1''').
(Process 8)
[0330] The compound of Formula (1) can also be prepared by the
following process in case that, for example, X is nitrogen atom, Z
is nitrogen atom, Y is oxygen atom, and U is carbon atom [i.e.
Compound (1''')]:
##STR00028##
wherein A, B, D, V, W, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and
L.sup.7 are as defined above.
[0331] Step 1-1 is a condensation reaction, and Step 1-2 is a
subsequent cyclization reaction. In the same manner as in Steps 3-1
and 3-2 of Process 4, the compound of Formula (4-5) and the
compound of Formula (8-1) can be condensed and then cyclized to
give the compound of Formula (1''').
(Process 9)
[0332] The compound of Formula (1) can also be prepared by the
following process in case that, for example, X is nitrogen atom, Z
is nitrogen atom, Y is oxygen atom, U is carbon atom, A is Formula
(A-3), and B is Formula (B-1) [i.e. the compound of Formula
(1''''')]:
##STR00029##
wherein o, p, q, V, W, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.8,
R.sup.9, L.sup.2, and L.sup.7 are as defined above; and L.sup.5 and
L.sup.11 are independently oxo group (provided that when L.sup.5 or
L.sup.11 is attached to the primary carbon atom, L.sup.5 or
L.sup.11 forms a formyl group with the attached carbon atom) or a
leaving group.
[0333] Step 1 and Step 1' are a condensation reaction followed by a
cyclization reaction. In the same manner as in Steps 3-1 and 3-2 of
Process 4, the compound of Formula (4-5) can be reacted with the
compound of Formula (9-1) or Formula (9-9) to give the compound of
Formula (9-2) or (9-4), respectively.
[0334] In case that L.sup.11 is a leaving group, Step 2 and Step 2'
is an alkylation reaction. In the same manner as in 1) Alkylation
step of Processes 2 and 3, the compound of Formula (9-2) can be
reacted with the compound of Formula (9-3) or Formula (9-8) to give
the compound of Formula (1''''') or Formula (1-2),
respectively.
[0335] In case that L.sup.11 is oxo group, Step 2 and Step 2' are a
reductive alkylation reaction. In the same manner as in 2)
Reductive alkylation step of Processes 2 and 3, the compound of
Formula (9-2) can be reacted with the compound of Formula (9-3) or
Formula (9-8) to give the compound of Formula (1''''') or Formula
(1-2), respectively.
[0336] Step 3 is a deprotection reaction. The compound of Formula
(9-4) is deprotected in the same manner as in the above-mentioned
L.sup.2 to give the compound of Formula (9-5).
[0337] In case that L.sup.5 is a leaving group, Step 4 and Step 5
are an alkylation reaction. In the same manner as in 1) Alkylation
step of Processes 2 and 3, the compounds of Formula (9-5) and
Formula (9-6), or the compounds of Formula (1-2) and Formula (9-7)
can be reacted to give the compound of Formula (1-2) or Formula
(1'''''), respectively.
[0338] In case that L.sup.5 is oxo group, Step 4 and Step 5 is a
reductive alkylation reaction. In the same manner as in 2)
Reductive alkylation step of Processes 2 and 3, the compounds of
Formula (9-5) and (9-6), or the compounds of Formula (1-2) and
Formula (9-7) can be reacted to give the compound of Formula (1-2)
or Formula (1'''''), respectively.
(Process 10)
[0339] The compound of Formula (2-1):
##STR00030##
wherein r, s, A, V, W, R.sup.2, R.sup.4, R.sup.5, R.sup.6,
R.sup.10, and R.sup.11 are as defined above can be prepared, for
example, in the same manner as in Reference Example 062 in case
that X and Y are nitrogen atom, Z is oxygen atom, and U is carbon
atom; in the same manner as in Reference Example 064 in case that X
is oxygen atom, Y and Z are nitrogen atom, and U is carbon atom;
and in the same manner as in Reference Example 063 in case that X
is oxygen atom, Y is nitrogen atom, and Z and U are carbon
atom.
[0340] In the above-explained processes, when any functional groups
other than the reactive site may be reacted under the explained
conditions or be unsuitable to carry out the explained processes,
the desired compound can be obtained by protecting the groups
except the reactive site, carrying out the reaction, and then
deprotecting it. The protecting group used herein includes, for
example, typical protecting groups described in the above-mentioned
Protective Groups in Organic Synthesis and the like. In specific,
the protecting group of amine includes, for example,
ethoxycarbonyl, tert-butoxycarbonyl, acetyl, and benzyl; and that
of hydroxy group includes, for example, tri(loweralkyl)silyl,
acetyl, and benzyl.
[0341] The protecting groups can be introduced and deprotected
according to commonly used methods in synthetic organic chemistry
(for example, see, the above-mentioned Protective Groups in Organic
Synthesis) or other similar methods.
[0342] In addition, when the functional groups of the intermediates
and the desired compounds in each process mentioned above are
modified appropriately, different compounds in the present
invention can be prepared. The functional group can be modified
according to conventional general-methods (for example, see,
Comprehensive Organic Transformations, R. C. Larock, 1989).
[0343] The starting materials and the intermediates in each of the
above processes are well-known compounds or can be synthesized from
well-known compounds according to well-known methods.
[0344] The intermediates and the desired compounds in each of the
above processes can be isolated and purified according to
commonly-used purification methods in synthetic organic chemistry
such as neutralization, filtration, extraction, washing, drying,
concentration, recrystallization, and various types of
chromatography. In addition, the intermediates may be used in the
next reaction without purification.
[0345] The optical isomers such as enantiomers, planar-chiral
forms, and axially chiral forms used herein can be
resolved/isolated by using well-known resolving steps (e.g. methods
using an optically active column, and fractionated crystallization)
in a suitable step in the above processes. In addition, optically
active substances may also be used as a starting material
herein.
[0346] In order to optically resolve the present compound or an
intermediate thereof having a basic group, the compound may, for
example, form a salt with an optically active acid (e.g.
monocarboxylic acids such as mandelic acid, N-benzyloxyalanine, and
lactic acid; dicarboxylic acids such as tartaric acid,
o-diisopropylidene tartrate, and malic acid; and sulfonic acids
such as camphorsulfonic acid and bromocamphorsulfonic acid) in an
inert solvent (e.g. alcohol solvents such as methanol, ethanol, and
2-propanol; ether solvents such as diethyl ether; ester solvents
such as ethyl acetate; aromatic hydrocarbon solvents such as
toluene; acetonitrile; and a mixed solvent thereof).
[0347] In case that the present compound or an intermediate thereof
has an acidic substituent such as carboxyl group, the compound may
be optically resolved by forming a salt thereof with an optically
active amine (e.g. organic amines such as .alpha.-phenethylamine,
kinin, quinidine, cinchonidine, cinchonine, and strychnine).
[0348] The temperature for forming the salt may be in the range of
room temperature to boiling point of the solvent. In order to
improve the optical purity, it is desirable to once raise the
temperature to around the boiling point of the solvent. The solvent
containing the crystallized salt can be optionally cooled before
the filtration to raise the yield thereof. The amount of the
optically active acid or amine used herein is in the range of about
0.5 equivalent to about 2.0 equivalents, and preferably around 1
equivalent per the substrate. The crystal can be optionally
recrystallized in an inert solvent (e.g. alcohol solvents such as
methanol, ethanol, and 2-propanol; ether solvents such as diethyl
ether; ester solvents such as ethyl acetate; aromatic hydrocarbon
solvents such as toluene; acetonitrile; and a mixed solvent
thereof) to obtain an optically active salt with high purity. If
necessary, the resultant salt can be treated with an acid or base
in a conventional method to obtain a free form thereof.
[0349] The compound of Formula (1) can be obtained in the form of a
free base or acid addition salt, depending on the types of the
functional group in the formula, selection of the starting
compound, and treatments/conditions of the reaction. Such free base
or acid addition salt can be transformed into the compound of
Formula (1) according to conventional methods. Meanwhile, the
compound of Formula (1) can be treated with various acids by using
conventional methods to obtain an acid addition salt thereof.
[0350] When it is necessary to obtain a salt of the present
compound, if the present compound is given in the form of a salt,
the resultant salt can be directly purified. On the other hand, if
the present compound is given in a free form, the compound can be
transformed to a salt thereof according to a conventional method by
dissolving or suspending the free form in a suitable organic
solvent, and then adding an acid or base thereto.
[0351] Furthermore, the present compound and a pharmaceutically
acceptable salt thereof may exist in an addition form with water or
various solvents, which are also comprised in the present
invention. Moreover, the present invention may encompass all
tautomers of the present compound, all possible stereoisomers of
the present compound, all optical isomers of the present compound,
and all aspects of crystals of the present compound.
[0352] The present compound or a pharmaceutically acceptable salt
thereof has a strong affinity and agonistic activity for
serotonin-4 receptor, which is explained below, and thus expected
to be a useful medicament for patients suffering from diseases or
symptoms which are desired and/or required to be treated with an
agonistic action or partial agonistic action for serotonin-4
receptor.
[0353] The diseases or symptoms which are desired and/or required
to be treated with an agonistic action or partial agonistic action
for serotonin-4 receptor include, for example, the following (i) to
(v):
(i) neuropsychiatric diseases such as Alzheimer-type dementia, Lewy
body dementia, vascular dementia, depression, posttraumatic stress
disorder (PTSD), memory impairment, anxiety, and schizophrenia;
(ii) digestive system diseases such as irritable bowel syndrome,
atonic constipation, habitual constipation, chronic constipation,
constipation induced by drugs (e.g. morphine and antipsychotic
drugs), constipation associated with Parkinson's disease,
constipation associated with multiple sclerosis, constipation
associated with diabetes mellitus, and constipation or dyschezia
caused by contrast materials taken as a pretreatment for endoscopic
examinations or barium enema X-ray examinations; (iii) digestive
system diseases such as functional dyspepsia, acute/chronic
gastritis, reflux esophagitis, gastric ulcer, duodenal ulcer,
gastric neurosis, postoperative paralytic ileus, senile ileus,
non-erosive reflux disease, NSAID ulcer, diabetic gastroparesis,
postgastrectomy syndrome, and intestinal pseudo-obstruction; (iv)
digestive system symptoms such as the digestive system diseases
mentioned in the above (ii) and (iii), scleroderma, diabetes
mellitus, anorexia in esophageal/biliary-tract diseases, nausea,
emesis, bloating, epigastric discomfort, abdominal pain, heartburn,
and belching; and (v) urinary system diseases associated with
dysuria such as urinary tract obstruction and prostatic
hyperplasia.
[0354] The present compound or a pharmaceutically acceptable salt
thereof is useful as a medicament for treating or preventing
especially the neuropsychiatric diseases such as Alzheimer-type
dementia mentioned in the above (i) because the compound shows an
excellent 5-HT.sub.4 receptor agonist activity and brain
penetration.
[0355] The present compound or a pharmaceutically acceptable salt
thereof may be orally or parenterally administered (e.g.
intravenous or subcutaneous administration; infusions;
intramuscular injections; subcutaneous injections; intranasal
formulations; eye-drops, suppositories; and transdermal
formulations such as ointments, creams, and lotions) for medical
use. A formulation for oral administration includes, for example,
tablets, capsules, pills, granules, powders, liquids, syrups and
suspensions; and a formulation for parenteral administration
includes, for example, injectable aqueous or oleaginous
suspensions, ointments, creams, lotions, aerosols, suppositories,
and adhesive skin patches.
[0356] These formulations can be formulated by using
conventionally-known techniques, and may comprise
conventionally-acceptable carriers, excipients, binders,
stabilizers, lubricants, disintegrants, etc. Moreover, the
formulation for injection may further comprise an acceptable
buffer, solubilizing agent, isotonic agent, etc. The formulation
may also optionally comprise flavoring agent.
[0357] The excipient used herein includes, for example, organic
excipients such as sugar derivative (e.g. lactose, white soft
sugar, glucose, mannitol, and sorbitol); starch derivatives (e.g.
corn starch, potato starch, .alpha.-starch, dextrin, and
carboxymethyl starch); cellulose derivatives (e.g. crystalline
cellulose, low-substituted hydroxy-propylcellulose, hydroxypropyl
methylcellulose, carboxymethylcellulose, carboxymethyl cellulose
calcium, and internally-cross-linked carboxymethylcellulose
sodium); acacia; dextran; and pullulan; and inorganic excipients
such as silicate derivatives (e.g. light anhydrous silicic acid,
synthetic aluminum silicate, and magnesium aluminometasilicate);
phosphates (e.g. calcium phosphate); carbonates (e.g. calcium
carbonate); and sulfates (e.g. calcium sulfate).
[0358] The lubricant used herein includes, for example, stearic
acid; metallic stearate such as calcium stearate, and magnesium
stearate; talc; colloid silica; waxes such as VEEGUM and
spermaceti; boric acid; adipic acid; sulfates such as sodium
sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; fatty
acid sodium salt; lauryl sulfates such as sodium lauryl sulfate and
magnesium lauryl sulfate; silicates such as anhydrous silicic acid
and silicic acid hydrate; and the above-mentioned starch
derivatives.
[0359] The binder used herein includes, for example,
polyvinylpyrrolidone, macrogol, and the substances defined in the
above-mentioned excipient.
[0360] The disintegrant used herein includes, for example, the
substances defined in the above-mentioned excipient, and
chemically-modified starches/celluloses such as croscarmellose
sodium, sodium carboxymethyl starch, and cross-linked
polyvinylpyrrolidone.
[0361] The stabilizer used herein includes, for example,
p-hydroxybenzoates such as methylparaben and propylparaben;
alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl
alcohol; benzalkonium chloride; phenols such as phenol and cresol;
thimerosal; dehydroacetic acid; and sorbic acid.
[0362] The flavoring agent used herein includes, for example,
commonly-used sweeteners, acidulants, and flavors.
[0363] A tablet for oral administration may comprise an excipient
together with various disintegrants as well as granulating binders.
Furthermore, a lubricant is often very useful for tablet
formulation. A similar type of the solid composition may be used as
a bulking agent of a gelatin capsule which may be combined by
various ingredients, preferably lactose (milk sugar) or
high-molecular-weight polyethylene glycol.
[0364] The active ingredient of aqueous suspension and/or elixir
for oral administration may be combined with a diluent together
with various sweetening agents, flavoring agents, coloring agents
or dyes, or if desired, emulsifiers and/or suspending agents. The
diluent includes water, ethanol, propylene glycol, glycerin and a
mixture thereof. The diluent is conveniently included in feed or
drinking water for animal in a concentration of 5 ppm to 5000 ppm,
and preferably 25 ppm to 5000 ppm.
[0365] A solution of the active ingredient for sterile injection
may be typically prepared for parenteral administration (e.g.
intramuscular, intraperitoneal, subcutaneous and intravenous use).
A solution of the present compound in, for example, sesame oil,
peanut oil or aqueous propylene glycol may be used. If necessary,
the aqueous solution may be appropriately adjusted or buffered to a
suitable pH, or prepared into an isotonic solution with a liquid
diluent. The aqueous solution can also be used for intravenous
injection. The oil solution can be also used for intra-articular,
intramuscular and subcutaneous injections. All of these solutions
may be prepared under sterile conditions by using conventional
formulation techniques known to those skilled in the art.
[0366] The present compound or a pharmaceutically acceptable salt
thereof for the intranasal or inhalation administration may be
provided in the solution or suspension form squeezed out or
released by a patient from a pump spray vessel, or as an aerosol
spray from a pressurized vessel or a nebulizer with using an
appropriate propellant including, for example,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide and other appropriate
gases. A dosage unit in the pressurized aerosol can be determined
by a bulb which provides a certain measured amount of the active
ingredient. A solution or suspension of the active compound may be
contained in the pressurized vessel or nebulizer.
[0367] A capsule and cartridge for an inhaler or insufflator (e.g.,
prepared from gelatin) may be formulated to contain the present
compound and a powder composition of appropriate powder bases
including, for example, lactose and starch.
[0368] The present compound or a pharmaceutically acceptable salt
thereof may be also formulated in a composition for the anus such
as a suppository or retention enema comprising conventional
suppository bases including, for example, cacao butter and other
glycerides.
[0369] A dosage of the present compound or a pharmaceutically
acceptable salt thereof depends on conditions, ages, administration
methods, etc., and for example, the dosage is 0.01 mg (preferably 1
mg) as a lower limit and 5000 mg (preferably 500 mg) as an upper
limit per day at one time or in several divided doses for adults
for oral administration, preferably depending on conditions. It is
expected to be effective in 0.01 mg (preferably 0.1 mg) as a lower
limit and 1000 mg (preferably 30 mg) as an upper limit per day at
one time or in several divided doses for adults for intravenous
administration depending on conditions.
[0370] The present compound or a pharmaceutically acceptable salt
thereof, or a pharmaceutical composition or formulation containing
the present compound may be optionally administered in combination
with other medicaments in order to treat the diseases defined
herein which are required to be treated with an agonistic action or
partial agonistic action for serotonin-4 receptor.
[0371] In specific, the present compound or a pharmaceutically
acceptable salt thereof, or a pharmaceutical composition or
formulation containing the present compound is expected to show
further efficacy in treating the various neuropsychiatric diseases
mentioned in the above (i), especially Alzheimer-type dementia, by
combining at least one of the following medicaments:
acetylcholinesterase inhibitors such as donepezil, galantamine,
rivastigmine, SNX-001 and NP-61; cholinesterase inhibitors such as
huperzine A; NMDA receptor antagonist such as memantine, dimebon
and neramexane; 5-HT6 receptor antagonists such as PF-5212365
(SAM-531), SB-742457, LU-AE58054, AVN-322, PF-05212377 (SAM-760)
and AVN101; .alpha.7nAChR agonists such as TC-5619, EVP-6124 and
GTS-21; .alpha.4.beta.2nACh receptor agonists such as AZD-1446 and
CHANTIX (varenicline); nAChR agonists such as ABT-089; AMPA
receptor agonists such as CX-717 and LY-451395; histamine H3
antagonists such as ABT-288, SAR-110894 and PF-03654746; muscarinic
M1 receptor agonists such as MCD-386 and GSK-1034702; PDE4
inhibitors such as etazolate; PDE9 inhibitors such as PF-04447943;
histone deacetylase inhibitors such as EVP-0334; .sigma.1 receptor
agonists such as Anavex-2-73; .gamma.-secretase inhibitors (GSI)
such as BMS-708163, NIC5-15, ELND-006, and MK-0752;
.gamma.-secretase modulators (GSM) such as E-2212 and CHF-5074;
A.beta. human monoclonal antibodies such as bapineuzumab,
solanezumab, PF-4360365 (ponezumab), gantenerumab (R-1450),
BAN-2401, MABT-5102A, RG-7412 and GSK-933776A; A.beta. vaccines
such as ACC-001 (PF-05236806), AD-02, CAD-106, V-950, UB-311 and
ACI-24; human immunoglobulins such as GAMMAGARD; A.beta.
aggregation inhibitors such as ELND-005 (AZD-103), PBT-2, NRM-8499
and Exebryl-1; tau aggregation inhibitors such as TRx-0014 and
LMTX; BACE inhibitors such as ACI-91, posiphen, CTS-21166, HPP-854
and LY-2886721; tyrosine kinase inhibitors such as masitinib;
GSK-3.beta. inhibitors/tau kinase inhibitors such as NP-12; RAGE
fusion proteins such as TTP-4000; ApoA-I/HDL-C elevations such as
RVX-208; other various agents showing neuroprotective action such
as SK-PC-B70M, T-817MA, davunetide, HF-0220, PF-4494700, PYM-50028,
CERE-110, ASP-0777, TAK-065, and AAD-2004; and other medicaments
used for treating various types of dementia.
EXAMPLE
[0372] Hereinafter, the present inventions are illustrated in more
detail with Reference Examples and Examples, but the technical
scope of the present inventions should not be construed to be
limited thereto. The compounds were identified by proton NMR
spectrum (.sup.1H-NMR), LC-MS, etc. Tetramethylsilane was used as
an internal standard for the NMR spectrum.
[0373] In addition, the compound names shown in the following
Reference Examples and Examples do not necessarily correspond to
those of IUPAC nomenclature.
[0374] The following abbreviations may be optionally used in
Reference Examples and Examples.
THF: Tetrahydrofuran
[0375] NaBH(OAc).sub.3: Triacetoxysodium borohydride
(Boc).sub.2O: Di-tert-butyldicarbonate
[0376] Pd(OH).sub.2: Palladium hydroxide
DMF: N,N-dimethylformamide
[0377] WSCI.HC1: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride HOBt.H.sub.2O: 1-hydroxybenzotriazole monohydrate
NMP: 1-Methyl-2-pyrrolidone TFA: Trifluoroacetic acid FA: Formic
acid CDCl.sub.3: Deuterated chloroform CD.sub.3OD: Deuterated
methanol DMSO-d.sub.6: Deuterated dimethylsulfoxide
Me: Methyl
Et: Ethyl
[0378] .sup.nPr: Normal propyl .sup.iPr: Isopropyl .sup.cPr:
Cyclopropyl .sup.nBu: Normal butyl .sup.iBu: Isobutyl .sup.cBu:
Cyclobutyl
Ph: Phenyl
Ac: Acetyl
Ms: Mesyl
Ts: Tosyl
[0379] Boc: tert-butoxycarbonyl
Pd--C: Palladium-carbon
[0380] NaBH.sub.3(CN): Sodium cyanoborohydride
Cbz or Z: Benzyloxycarbonyl
[0381] CH.sub.2Cl.sub.2:Methylene chloride Ns:
Nosyl(2-nitrobenzenesulfonyl)
SEM: 2-(Trimethylsilyl)ethoxymethyl
NEt.sub.3: Triethylamine
[0382] CDI: N,N'-carbonylimidazole TBAF: Tetrabutylammonium
fluoride
MeO or OMe: Methoxy
[0383] BBr.sub.3: Boron tribromide LiHMDS: Lithium
hexamethyldisilazide BINAP:
2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl DMAP:
N,N-dimethyl-4-aminopyridine p.o.: Peroral administration
s: Singlet
d: Doublet
t: Triplet
q: Quartet
m: Multiplet
br: Broad
[0384] dd: Double doublet td: Triple doublet J: Coupling
constant
Hz: Hertz
[0385] N: Normal (e.g. 2 N HCl means 2 normal of HCl) M: Molar
concentration (mol/L) (e.g. 2 M methylamine means 2 mol/L of
methylamine solution)
min: Minute
atm: Atmosphere
[0386] The isolation/purification by a reverse-phase HPLC herein
was carried out under the following conditions:
Condition FA: (TFA or FA as an additive)
Instrument: Shimadzu & Gilson215
Column: Grace Vydac C18, 200.times.25 mm, 5 .mu.m
[0387] Flow rate: 30 ml/min Column temperature: 40.degree. C.
Moving bed A1: Distilled water (containing 0.075% TFA, v/v) Moving
bed A2: Distilled water (containing 0.2% FA, v/v)
Moving bed B: Acetonitrile
[0388] Condition FB: (Basic or neutral condition)
Instrument: Shimadzu & Gilson215
Column: Durashell C18, 200.times.25 mm, 5 .mu.m
[0389] Flow rate: 30 ml/min Column temperature: 30.degree. C.
Moving bed A1: Distilled water (containing 0.05% ammonia, v/v)
Moving bed A2: Distilled water
Moving bed B: Acetonitrile
Condition FC: (TFA)
Instrument: Shimadzu & Gilson281
Column: YMC ODS-AQ, 150.times.30 mm, 5 .mu.m
[0390] Flow rate: 28 ml/min Column temperature: 40.degree. C.
Moving bed A: Distilled water (containing 0.075% TFA, v/v) Moving
bed B: Acetonitrile (containing 0.025% TFA, v/v)
Condition FD: (TFA)
Instrument: Gilson215
Column: YMC ODS-AQ, 150.times.30 mm, 5 .mu.m
[0391] Flow rate: 28 ml/min Column temperature: 40.degree. C.
Moving bed A: Distilled water (containing 0.075% TFA, v/v) Moving
bed B: Acetonitrile (containing 0.025% TFA, v/v)
Condition FE: (TFA)
Instrument: Gilson281
Column: Synergi max RP, 150.times.30 mm, 5 .mu.m
[0392] Flow rate: 25 ml/min Column temperature: 40.degree. C.
Moving bed A: Distilled water (containing 0.075% TFA, v/v) Moving
bed B: Acetonitrile (containing 0.025% TFA, v/v)
[0393] LC/MS analytic conditions for identifying compounds are as
follows.
High performance liquid chromatograph mass spectrometer; Measuring
conditions of LCMS are as follows. The observed values of mass
spectrometry, i.e. [MS (m/z)], are shown as [M+H].sup.+. In case
that the analyzed compound is a salt thereof, unless otherwise
noted, M means a mass number of the free base thereof.
Measurement Method A:
[0394] Detection instrument: API Agilent 1100 Series (manufactured
by Applied Biosystems) HPLC: API150EX LC/MS system (manufactured by
Applied Biosystems)
Column: YMC CombiScreen ODS-A (S-5 .mu.m, 12 nm, 4.6.times.50
mm)
Solvent: Solution A: 0.05% TFA/H.sub.2O,
[0395] Solution B: 0.035% TFA/MeOH
Gradient Condition:
0.0-1.0 min A 75% (B 25%)
[0396] 1.0-4.7 min Linear gradient from A 75% to 1% (B 25% to
99%)
4.7-5.7 min A 1% (B 99%)
[0397] 5.7-6.1 min Linear gradient from A 1% to 75% (B 99% to
25%)
6.1-7.1 min A 75% (B 25%)
[0398] 7.1-7.2 min Linear gradient from A 75% to 100% (B 25% to 0%)
Flow rate: 2.4 mL/min
UV: 220 nm
Measurement Method B:
[0399] LC-MS: Waters ACQUITY.TM. UltraPerformance LC
Column: Waters ACQUITY UPLC BEH Phenyl 1.7 .mu.m, 2.1.times.50
mm
[0400] Solvent: Solution A: 0.05% formic acid/H.sub.2O, Solution B:
0.05% formic acid/CH.sub.3CN
Gradient Condition:
[0401] 0.0 min; A/B=90:10 0.0-1.3 min; A/B=90:10-1:99 (linear
gradient) 1.3-1.5 min; A/B=1:99 1.5-2.0 min; A/B=90:10 Flow rate:
0.75 mL/min
UV: 220, 254 nm
[0402] Column temperature: 40.degree. C.
Measurement Method C:
[0403] LCMS: Shimadzu LCMS-2010EV
Column: Shiseido CAPCELL PAK C18 MGII (4.6 mm.times.50 mm)
Solvent: Solution A: MeOH, Solution B: 0.05% TFA/H.sub.2O
Gradient Condition:
[0404] 0.0-1.0 min; A/B=30:70 1.0-7.0 min; A/B=99:1 7.1-12.0 min;
A/B=30:70 Flow rate: 2.8 mL/min
UV: 220 nm
[0405] Column temperature: 40.degree. C.
Measurement Method D:
[0406] LCMS: Shimadzu LCMS-2010EV
Column: Ximate C18 3.0 m 2.1 mm.times.30 mm
Solvent: Solution A: 0.019% TFA/H.sub.2O,
[0407] Solution B: 0.038% TFA/CH.sub.3CN
Gradient Condition:
[0408] 0.0 min; A/B=90:10 0.0-1.35 min; A/B=20:80 1.35-2.25 min;
A/B=20:80 2.25-2.26 min; A/B=90:10 2.26-3.00 min; A/B=90:10 Flow
rate: 0.8 mL/min
UV: 220 nm
[0409] Column temperature: 50.degree. C.
Measurement Method E:
[0410] LCMS: Shimadzu LCMS-2020
Column: Phenomenex Kinetex 1.7 .mu.m C18 (50 mm.times.2.10 mm)
Solvent: Solution A: MeOH,
[0411] Solution B: 0.05% TFA/H.sub.2O
Gradient Condition:
[0412] 0.0 min; A/B=30:70 0.0-1.90 min; A/B=99:1 1.91-3.00 min;
A/B=30:70 Flow rate: 0.5 mL/min
UV: 220 nm
[0413] Column temperature: 40.degree. C.
[0414] The NMR measurements herein were carried out by using JEOL
JNM-AL LA 300 and AL 400.
[0415] The starting compounds, reagents, and solvents used herein
are commercially available, unless otherwise noted.
Reference Example 001
Preparation of 3-(propan-2-yl)-1H-indazole
##STR00031##
[0417] (1) 2-Aminobenzonitrile (6.5 g) was dissolved in diethyl
ether (25 ml). To the solution was added dropwise 2 N
isopropylmagnesium chloride in diethyl ether (76 ml) with stirring
at 0.degree. C., and then the solution was further stirred at
0.degree. C. for 5 hours. To the reaction solution was added
dropwise 10% aqueous hydrochloric acid (115 ml) with stirring at
0.degree. C., and then the solution was further stirred for 1 hour.
The reaction solution was basified by adding sodium hydroxide (19.3
g) thereto with stirring at 0.degree. C., and the resultant
solution was extracted with diethyl ether. The organic layer was
washed with brine, dried over sodium sulfate and filtered, and then
the filtrate was concentrated under reduced pressure to give
1-(2-aminophenyl)-2-methylpropan-1-one (8.85 g) as a brownish-red
oil.
[0418] LC-MS, m/z; 164 [M+H]+
[0419] (2) The above-prepared compound (5 g) was dissolved in
concentrated hydrochloric acid (25 ml). To the solution was added
dropwise sodium nitrite (2.4 g) dissolved in water (12 ml) with
stirring at 0.degree. C., and then the mixed solution was further
stirred at 0.degree. C. for 1 hour. To the reaction solution was
added dropwise tin (II) chloride dihydrate (16.5 g) dissolved in
concentrated hydrochloric acid (12 ml), and then the solution was
stirred at 0.degree. C. for hours. The reaction solution was
extracted with dichloromethane, the organic layer was washed with
brine, dired over sodium sulfate and filtered, and then the
filtrate was concentrated under reduced pressure. The residue was
purified by silica-gel chromatography (developing solvent:
hexane/ethyl acetate=2:1) to give the title compound (4.3 g) as a
white solid.
[0420] LC-MS, m/z; 161 [M+H]+
[0421] The compounds in the following table (i.e. Reference
Examples 002 to 012) were prepared in the same manner as in
Reference Example 001 except that the 2-aminobenzonitrile and the
isopropylmagnesium chloride were replaced with the corresponding
starting compound and Grignard reagent defined as R.sup.3MgX
wherein X is halogen atom, respectively.
##STR00032##
TABLE-US-00001 TABLE 1 Ref. Compound Ex. R.sup.3 R.sup.4 R.sup.5
R.sup.6 R.sup.7 Name LC-MS, m/z 002 Et H H H H 3-ethyl-1H- LC-MS,
m/z; indazole 147 [M + H]+ 003 Et F H H H 3-ethyl-4- LC-MS, m/z;
fluoro-1H- 165 [M + H]+ indazole 004 Et H F H H 3-ethyl-5- LC-MS,
m/z; fluoro-1H- 165 [M + H]+ indazole 005 Et H H F H 3-ethyl-6-
LC-MS, m/z; fluoro-1H- 165 [M + H]+ indazole 006 Et H H H F
3-ethyl-7- LC-MS, m/z; fluoro-1H- 165 [M + H]+ indazole 007
##STR00033## H H H H 3-(2- methylpropyl)- 1H-indazole LC-MS, m/z;
175 [M + H]+ 008 Me H H H H 3-methyl-1H- LC-MS, m/z; indazole 133
[M + H]+ 009.sup.1) ##STR00034## H H H H 3-cyclobutyl- 1H-indazole
LC-MS, m/z; 173 [M + H]+ 010 .sup.iPr H H H F 7-fluoro-3- LC-MS,
m/z; (propan-2- 179 [M + H]+ yl)-1H- indazole 011 Et H H MeO H
3-ethyl-6- LC-MS, m/z; methoxy-1H- 177 [M + H]+ indazole 012 Et H H
H Cl 7-chloro-3- LC-MS, m/z; ethyl-1H- 225 [M + HCOO]- indazole
.sup.1)The Grignard reagent used herein was prepared from
bromocyclobutane and magnesium.
Reference Example 013
Preparation of 3-cyclopropyl-1H-indazole
##STR00035##
[0423] (1) To 1N boron trichloride/methylene chloride solution (100
ml) was added 1,2-dichloroethane (100 ml). The mixed solution was
cooled to 0.degree. C. to 5.degree. C., and aniline (9.3 g) was
added thereto. To the reaction solution was added
cyclopropylcyanide (10 g) and aluminum chloride (14.4 g). The
mixture was warmed to room temperature and methylene chloride was
removed out at 70.degree. C. The reaction solution was refluxed for
18 hours and then cooled in an ice bath, water was added thereto,
and the mixture was extracted with methylene chloride (100 ml). The
organic layer was dried over sodium sulfate and filtered, and the
filtrate was concentrated under reduced pressure to give
(2-aminophenyl)(cyclopropyl)methanone (5.0 g).
[0424] (2) The above-prepared compound was treated in the same
manner as in Reference Example 001 (2) to give the title
compound.
[0425] LC-MS, m/z; 159 [M+H]+
Reference Example 014
Preparation of 3-(methoxymethyl)-1H-indazole
##STR00036##
[0426] [SEM: 2-(Trimethylsilyl)ethoxymethyl]
[0427] (1)
1-{[2-(Trimethylsilyl)ethoxy]methyl}-1H-indazole-3-carboxylic
methyl ester
[0428] To a suspension of sodium hydride (2.23 g, 55% in silicone
oil) in THF (70 ml) was added dropwise indazole-3-carboxylic methyl
ester (3.0 g) in THF (30 ml) at 0.degree. C., and the mixture was
stirred at the same temperature for 1 hour. To the reaction
solution was added dropwise 2-(trimethylsilyl)ethoxymethyl chloride
(3.62 ml) at 0.degree. C., and the mixture was further stirred at
the same temperature for 1.5 hours. To the reaction solution was
added water (200 ml), and the solution was extracted with ethyl
acetate (200 ml). The organic layer was washed with brine (100 ml),
dried over sodium sulfate, and concentrated under reduced pressure.
The residue was purified by silica-gel chromatography (column;
Hi-Flash.TM., developing solvent: hexane/ethyl acetate) to give the
title compound (5.06 g).
[0429] LC-MS, m/z; 307 [M+H]+ [0430] (2)
(1-{[2-(Trimethylsilyl)ethoxy]methyl}-1H-indazole-3-yl)methanol
[0431] Under nitrogen atmosphere, lithium aluminium hydride (1.57
g) was suspended in tetrahydrofuran (70 ml). To the suspension was
added dropwise
1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-3-carboxylic
methyl ester (5.06 g) in tetrahydrofuran (30 ml) at -40.degree. C.,
and the mixture was stirred at the same temperature for 2 hours. To
the reaction solution was added sodium fluoride (6.93 g), added
dropwise water (2.97 ml), and then added dichloromethane (150 ml).
The insoluble residue was removed by Celite filtration, and the
filtrate was concentrated under reduced pressure to give the title
compound (3.61 g) as an oil. [0432] (3)
3-(Methoxymethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole
[0433]
(1-{[2-(Trimethylsilyl)ethoxy]methyl}-1,4-indazole-3-yl)methanol
(2.0 g) was dissolved in tetrahydrofuran (40 ml). To the solution
was added sodium hydride (0.53 mg, 55% in silicone oil) at
0.degree. C., and then the mixture was stirred for 1 hour at room
temperature. To the reaction solution was added dropwise methyl
iodide (805 .mu.l) at 0.degree. C., and the solution was stirred at
room temperature overnight. To the reaction solution was added
saturated sodium bicarbonate aqueous solution (200 ml). The mixed
solution was extracted with ethyl acetate (200 ml). The organic
layer was further washed with brine (100 ml), dried over magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica-gel chromatography (column; Hi-Flash.TM.,
developing solvent: hexane/ethyl acetate) to give the title
compound (1.35 g). [0434] (4) 3-(Methoxymethyl)-1H-indazole
[0435] To
3-(methoxymethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazo-
le (2.35 g) in tetrahydrofuran (10 ml) were added 1M
tetrabutylammonium fluoride/tetrahydrofuran (121 ml) and
ethylenediamine (4.05 ml), and the mixture was stirred under reflux
for 5 days. The reaction solution was cooled to room temperature,
water was added thereto, and the resultant solution was extracted
with ethyl acetate (.times.3). The organic layer was dried over
sodium sulfate and concentrated under reduced pressure, and the
residue was purified by silica-gel chromatography (column;
Hi-Flash.TM., developing solvent: hexane/ethyl acetate) to give the
title compound (0.96 g).
[0436] LC-MS, m/z; 163 [M+H]+
Reference Example 015
Preparation of 3-(difluoromethyl)-1H-indazole
##STR00037##
[0438] To a mixed solution of Deoxo-Fluor (1.57 ml) and
dichloromethane (2.0 ml) were added 1H-indazole-3-carboaldehyde
(0.73 g) in dichloromethane (2.0 ml) and ethanol (58 .mu.l) at
0.degree. C., and the solution was stirred for 1 hour at room
temperature. To the reaction solution was added saturated sodium
bicarbonate aqueous solution (50 ml) at 0.degree. C., and the mixed
solution was extracted with ethyl acetate (50 ml) and then further
washed with water (50 ml).
[0439] The organic layer was dried over sodium sulfate and
concentrated under reduced pressure, and then the residue was
purified by silica-gel chromatography (column; Hi-Flash.TM.,
developing solvent: hexane/ethyl acetate) to give the title
compound (0.27 g).
[0440] LC-MS, m/z; 167 [M-E]
Reference Example 016
Preparation of
3-ethyl-6-fluoro-N'-hydroxy-1H-indazole-1-carboximidamide
##STR00038##
[0442] (1) 3-Ethyl-6-fluoro-1H-indazole (0.95 g) was dissolved in
dichloromethane (15 ml). To the solution were added triethylamine
(1.21 ml), N,N-dimethyl-4-aminopyridine (170 mg) and cyanogen
bromide (674 mg), and the mixture was stirred at room temperature
for 3.5 hours. The reaction solution was concentrated under reduced
pressure, and the resultant crude-product was used for the next
reaction.
[0443] (2) The above crude-product was suspended in a mixed solvent
of THF/water (10/1) (15 ml). To the suspension were added
hydroxylamine hydrochloride (523 mg) and triethylamine (1.61 ml),
and the mixture was stirred for 1.5 hours with heating at
60.degree. C. and then cooled to room temperature. To the reaction
solution was added water (50 ml), and the mixture was extracted
with ethyl acetate (50 ml) and then washed with brine (50 ml). The
organic layer was dried over sodium sulfate and concentrated under
reduced pressure to give the crude product of the title compound
(1.29 g).
[0444] LC-MS, m/z; 223 [M+H]+
[0445] The compounds in the following table (i.e. Reference
Examples 017 to 032) were prepared in the same manner as in
Reference Example 016 except that the 3-ethyl-6-fluoro-1H-indazole
was replaced with the corresponding starting compound (which is
commercially available or described in Reference Examples 001 to
015).
##STR00039##
TABLE-US-00002 TABLE 2 Ref. Compound .sup.1H-NMR/LC-MS, Ex. R.sup.3
R.sup.4 R.sup.5 R.sup.6 R.sup.7 Name m/z 017 .sup.iPr H H H H
N'-hydroxy-3- LC-MS, m/z; (propan-2-yl)- 219 [M + H]+
1H-indazole-1- carboximidamide 018 Et H H H H 3-ethyl-N'-
hydroxy-1H- LC-MS, m/z; indazole-1- 205 [M + H]+ H carboximidamide
019 ##STR00040## H H H 3-cyclopropyl- N'-hydroxy-1H- indazole-1-
carboximidamide LC-MS, m/z; 217 [M + H]+ 020 Et F H H H 3-ethyl-4-
LC-MS, m/z; fluoro-N'- 223 [M + H]+ hydroxy-1H- indazole-1-
carboximidamide 021 Et H F H H 3-ethyl-5- LC-MS, m/z; fluoro-N'-
223 [M + H]+ hydroxy-1H- indazole-1- carboximidamide 022 Et H H H F
3-ethyl-7- LC-MS, m/z; fluoro-N'- 223 [M + H]+ hydroxy-1H-
indazole-1- carboximidamide 023 ##STR00041## H H H H
N'-hydroxy-3-(2- methylpropyl)- 1H-indazole-1- carboximidamide
LC-MS, m/z; 233 [M + H]+ 024 Me H H H H N'-hydroxy-3- LC-MS, m/z;
methyl-1H- 191 [M + H]+ indazole-1- carboximidamide 025
##STR00042## H H H H 3-cyclobutyl-N'- hydroxy-1H- indazole-1-
carboximidamide .sup.lH-NMR (400 MHz, CDCl.sub.3): (.delta.
1.88-2.01 (m, 1H), 2.02-2.18 (m, 1H), 2.36- 2.51 (m, 4H), 3.80-3.91
(m, 1H), 5.57 (s, 1H), 7.06 (t, J = 7.5 Hz, 1H), 7.38 (t, J = 7.6
Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H). 026
.sup.iPr H H H F 7-fluoro-N'- LC-MS, m/z; hydroxy-3- 237 [M + H]+
(propan-2-yl)- 1H-indazole-1- carboximidamide 027 Et H H MeO H
3-ethyl-N'- LC-MS, m/z; hydroxy-6- 235 [M + H]+ methoxy-1H-
indazole-1- carboximidamide 028 Et H H H Cl 7-chloro-3- LC-MS, m/z;
ethyl-N'- 239 [M + H]+ hydroxy-1H- indazole-1- carboximidamide 029
##STR00043## H H H H N'-hydroxy-3- (methoxymethyl)- 1H-indazole-1-
carboximidamide LC-MS, m/z; 221 [M + H]+ 030 ##STR00044## H H H H
3- (difluoromethyl)- N'-hydroxy-1H- indazole-1- carboximidamide
LC-MS, m/z; 227 [M + H]+ 031 Cl H H H H 3-chloro-N'- LC-MS, m/z;
hydroxy-1H- 211 [M + H]+ indazole-1- carboximidamide 032 Br H H H H
3-bromo-N'- LC-MS, m/z; hydroxy-1H- 255 [M + H]+ indazole-1-
carboximidamide
Reference Example 033
Preparation of tert-butyl
4-[3-(3-ethyl-6-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidine-1-
-carboxylate
##STR00045##
[0447] 1-(Tert-butoxycarbonyl)piperidine-4-carboxylic acid (1.46 g)
was dissolved in THF (10 ml). To the solution was added
N,N'-carbonylimidazole (1.03 g), and the mixed solution was stirred
at room temperature for 1 hour. To the reaction solution was added
dropwise 3-ethyl-6-fluoro-N'-hydroxy-1H-indazole-1-carboximidamide
(1.29 g) in THF (10 ml), and the mixture was stirred at room
temperature overnight. To the mixture was added 1M
tetrabutylammonium fluoride in THF (6.95 ml), and the mixture was
stirred at 50.degree. C. for 1.5 hours. The reaction solution was
concentrated under reduced pressure, and the residue was purified
by silica-gel chromatography (column; Hi-Flash.TM., developing
solvent: hexane/ethyl acetate) to give the title compound (1.66
g).
[0448] LC-MS, m/z; 460 [M+HCOO]-
[0449] The compounds in the following table (i.e. Reference
Examples 034 to 043) were prepared in the same manner as in
Reference Example 033 except that the
3-ethyl-6-fluoro-N'-hydroxy-1,4-indazole-1-carboximidamide was
replaced with the corresponding starting compound (which is
described in Reference Examples 016 to 032).
##STR00046##
TABLE-US-00003 TABLE 3 Ref. Compound Ex. R.sup.3 R.sup.4 R.sup.5
R.sup.6 R.sup.7 Name LC-MS, m/z 034 Et F H H H tert-butyl 4-[3-
LC-MS, m/z; (3-ethyl-4- 460 [M + HCOO]- fluoro-1H- indazol-1-yl)-
1,2,4-oxadiazol- 5-yl]piperidine- 1-carboxylate 035 Et H F H H
tert-butyl 4-[3- LC-MS, m/z; (3-ethyl-5- 460 [M + HCOO]- fluoro-1H-
indazol-1-yl)- 1,2,4-oxadiazol- 5-yl]piperidine- 1-carboxylate 036
Et H H H F tert-butyl 4-[3- LC-MS, m/z; (3-ethyl-7- 460 [M + HCOO]-
fluoro-1H- indazol-1-yl)- 1,2,4-oxadiazol- 5-yl]piperidine-
1-carboxylate 037 ##STR00047## H H H H tert-butyl 4-{3- [3-(2-
methylpropyl)-1H- indazol-1-yl]- 1,2,4-oxadiazol- 5-yl}piperidine-
1-carboxylate LC-MS, m/z; 470 [M + HCOO]- 038 .sup.iPr H H H F
tert-butyl 4-{3- LC-MS, m/z; [7-fluoro-3- 474 [M + HCOO]-
(propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol- 5-yl}piperidine-
1-carboxylate 039 Et H H MeO H tert-butyl 4-[3- LC-MS, m/z;
(3-ethyl-6- 472 [M + HCOO]- methoxy-1H- indazol-1-yl)-
1,2,4-oxadiazol- 5-yl]piperidine- 1-carboxylate 040 Et H H H Cl
tert-butyl 4-[3- LC-MS, m/z; (7-chloro-3- 432 [M + H]+
ethyl-1H-indazol- 1-yl)-1,2,4- oxadiazo1-5- yl]piperidine-1-
carboxylate 041 ##STR00048## H H H H tert-butyl 4-{3- [3-
(methoxymethyl)- 1H-indazol-1-yl]- 1,2,4-oxadiazol-
5-yl}piperidine- 1-carboxylate No data 042 ##STR00049## H H H H
tert-butyl 4-{3- [3- (difluoromethyl)- 1H-indazol-1-yl]-
1,2,4-oxadiazol- 5-yl}piperidine- 1-carboxylate LC-MS, m/z; 420 [M
+ H]+ 043 Br H H H H tert-butyl 4-[3- LC-MS, m/z; (3-bromo-1H- 448
[M + H]+ indazol-1-yl)- 1,2,4-oxadiazol- 5-yl]piperidine-
1-carboxylate
Reference Example 044
Preparation of tert-butyl
4-{3-[3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}piperidine-1--
carboxylate
##STR00050##
[0451] 1-(Tert-butoxycarbonyl)piperidine-4-carboxylic acid (0.54 g)
was dissolved in DMF (5 ml). To the solution was added
N,N'-carbonylimidazole (0.38 g), and the mixed solution was stirred
at room temperature for 2 hours. To the reaction solution was added
N'-hydroxy-3-(propan-2-yl)-1H-indazole-1-carboximidamide (0.49 g),
and the mixed solution was stirred at 110.degree. C. for 20 hours
and then cooled to room temperature. To the reaction solution was
added water, and the mixture was extracted with ethyl acetate. The
organic layer was washed with water and brine, dried over sodium
sulfate and filtered, and the filtrate was concentrated under
reduced pressure. The residue was purified by silica-gel
chromatography (developing solvent: hexane/ethyl acetate=6/1) to
give the title compound (0.64 g).
[0452] LC-MS, m/z; 412 [M+H]+
[0453] The compounds in the following table (i.e. Reference
Examples 045 to 049) were prepared in the same manner as in
Reference Example 044 except that the
NT-hydroxy-3-(propan-2-yl)-1H-indazole-1-carboximidamide was
replaced with the corresponding starting compound (which is
described in Reference Examples 016 to 032).
##STR00051##
TABLE-US-00004 TABLE 4 Com- Ref. pound LC-MS, Ex. R.sup.3 R.sup.4
R.sup.5 R.sup.6 R.sup.7 Name m/z 045 Et H H H H tert-butyl 4-
LC-MS, [3- m/z; (3-ethyl-1H- 398 indazol-1- [M + H]+ yl)-1,2,4-
oxadiazol- 5- yl]piperidine- 1-carboxylate 046 ##STR00052## H H H H
tert-butyl 4- [3-(3- cyclopropyl- 1H-indazol- 1-yl)-1,2,4-
oxadiazol- 5-yl] piperidine- 1-carboxylate LC-MS, m/z; 432 [M +
Na]+ sodium adduct 047 Me H H H H tert-butyl 4- LC-MS, [3- m/z;
(3-methyl- 384 1H- [M + H]+ indazol-1- yl)- 1,2,4- oxadiazol- 5-
yl]piperidine- 1-carboxylate 048 ##STR00053## H H H H tert-butyl 4-
[3-(3- cyclobutyl- 1H- indazol-1- yl)-1,2,4- oxadiazol- 5-
yl]piperidine- 1-carboxylate LC-MS, m/z; 446 [M + Na]+ sodium
adduct 049 Cl H H H H tert-butyl 4- LC-MS, [3- m/z; (3-chloro- 404
1H- [M + H]+ indazol-1- yl)- 1,2,4- oxadiazol- 5-yl] piperidine-
1-carboxylate
[0454] The compounds in the following table (i.e. Reference
Examples 050 to 052) were prepared in the same manner as in
Reference Example 044 except that the
N'-hydroxy-3-(propan-2-yl)-1H-indazole-1-carboximidamide and the
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid were replaced
with the corresponding starting compound and
1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid,
respectively.
##STR00054##
TABLE-US-00005 TABLE 5 Ref. Ex. R.sup.3 R.sup.4 R.sup.5 R.sup.6
R.sup.7 Compound Name LC-MS, m/z 050 Et H H H H tert-butyl 3-[3-
LC-MS, m/z; (3-ethyl-1H- 313 [M - tBu + H]+ indazol-1-yl)- des tBu
1,2,4-oxadiazol- 5-yl]azetidine-1- carboxylate 051 .sup.iPr H H H H
tert-butyl 3-{3- LC-MS, m/z; [3-(propan-2-yl)- 344 [M - tBu +
1H-indazol-1-yl]- NH4]+ des tBu, 1,2,4-oxadiazol- ammonia
5-yl}azetidine-1- adduct carboxylate 052 Et H H F H tert-butyl
3-[3- LC-MS, m/z; (3-ethyl-6- 331 [M - tBu + H]+ fluoro-1H-
indazol-1-yl)- 1,2,4-oxadiazol- 5-yl]azetidine-1- carboxylate
Reference Example 053
Preparation of tert-butyl
4-(2-iodoethyl)piperidine-1-carboxylate
##STR00055##
[0456] Tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (2.29
g) was dissolved in methylene chloride (40 ml). To the solution
were added iodine (3.05 g), triphenylphosphine (3.41 g) and
imidazole (1.02 g), and the mixture was stirred at room temperature
overnight. The reaction solution was concentrated under reduced
pressure. To the residue were added methylene chloride (3 ml) and
diethyl ether (3 ml), and the precipitated insoluble-matter was
removed by filtration. The filtrate was concentrated under reduced
pressure, and the residue was purified by silica-gel chromatography
(developing solvent: hexane/ethyl acetate=5/1) to give tert-butyl
4-(2-iodoethyl)piperidine-1-carboxylate (3.00 g) as a colorless
oil.
[0457] LC-MS, m/z; 340 [M+H]+
Reference Example 054
Preparation of tert-butyl
3-({[(4-methylphenyl)sulfonyl]oxy}methyl)piperidine-1-carboxylate
##STR00056##
[0459] Tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (166 g)
was dissolved in toluene (1.2 L). To the solution were added
trimethylamine hydrochloride (7.37 g) and triethylamine (161 ml).
To the mixture was slowly added 4-methylbenzenesulfonyl chloride
(176 g) at 0.degree. C. with stirring, and then the resultant
mixture was stirred at room temperature for 6 hours. The reaction
solution was washed sequentially with 30% citric acid aqueous
solution, water, and brine. The organic layer was dried over sodium
sulfate and filtered, and the filtrate was concentrated under
reduced pressure. To the residue were added tert-butyl methyl ether
(5 ml) and hexane (800 ml), and the mixture was stirred at room
temperature for 2 hours. The resulting crystal was collected on a
filter to give tert-butyl
3-({[(4-methylphenyl)sulfonyl]oxy}methyl)piperidine-1-carboxylate
(234.5 g) as a white solid.
[0460] LC-MS, m/z; 370 [M+H]+.
Reference Example 055
Preparation of tert-butyl
(3S)-3-(iodomethyl)pyrrolidine-1-carboxylate
##STR00057##
[0462] (1) (3S)-1-(Tert-butoxycarbonyl)pyrrolidine-3-carboxylic
acid (10 g) was dissolved in tetrahydrofuran (100 ml). To the
solution was added dropwise dimethyl sulfide-borane tetrahydrofuran
solution (54 ml) at 0.degree. C. with stirring, and then the
mixture was warmed to room temperature and stirred for 3 hours. To
the reaction solution was added dropwise methanol (100 ml) at
0.degree. C. with stirring, and then the reaction solution was
concentrated under reduced pressure. The residue was purified by
silica-gel chromatography (developing solvent: hexane/ethyl
acetate=1:9) to give
tert-butyl(3S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (7.8 g)
as a colorless oil.
[0463] LC-MS, m/z; 202 [M+H]+.
[0464] (2) The above-prepared compound (7.8 g) was dissolved in
dichloromethane (150 ml). To the solution were added
triphenylphosphine (13.3 g), imidazole (3.96 g) and iodine (11.8
g), and the mixture was stirred at 70.degree. C. for 3 hours. To
the reaction solution was added saturated sodium thiosulfate
aqueous solution. The mixed solution was extracted with chloroform.
The organic layer was washed with brine, dried over sodium sulfate
and filtered, and the filtrate was concentrated under reduced
pressure. The residue was purified by silica-gel chromatography
(developing solvent: hexane/ethyl acetate=11:1) to give the title
compound (11.5 g) as a white solid.
[0465] LC-MS, m/z; 312 [M+H]+
Reference Example 056
Preparation of tert-butyl
(3R)-3-(iodomethyl)pyrrolidine-1-carboxylate
##STR00058##
[0467] The title compound was prepared in the same manner as in
Reference Example 055 except that the
(3S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid was
replaced with (3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic
acid.
[0468] LC-MS, m/z; 312 [M+H]+
Reference Example 057
Preparation of methyl(3-chloropropyl)methylcarbamate
##STR00059##
[0470] 3-Chloro-N-methylpropane-1-amine (0.576 g) was dissolved in
dichloromethane (9 ml). To the solution was added triethylamine
(1.4 ml) at room temperature with stirring. To the reaction
solution was added dropwise methyl chlorocarbonate (0.454 g), and
the mixed solution was stirred at room temperature for 4 hours. To
the reaction solution was added water. The mixture was extracted
with ethyl acetate, the organic layer was washed with brine, dried
over sodium sulfate and filtered, and the filtrate was concentrated
under reduced pressure to give
methyl(3-chloropropyl)methylcarbamate.
[0471] LC-MS, m/z; 166 [M+H]+
Reference Example 058
Preparation of methyl(2-bromoethyl)carbamate
##STR00060##
[0473] The title compound was prepared in the same manner as in
Reference Example 057 except that the
3-chloro-N-methylpropane-1-amine was replaced with
2-bromoethaneamine.
[0474] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 3.45 (t, J=5.6
Hz, 2H), 3.56 (t, J=5.72 Hz, 2H), 3.66 (s, 3H), 5.24 (s, 1H).
Reference Example 059
Preparation of
4-[3-(3-ethyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]cyclohexanone
##STR00061##
[0476] The title compound was prepared in the same manner as in
Reference Example 033 except that the
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid and the
3-ethyl-6-fluoro-N'-hydroxy-1H-indazole-1-carboximidamide were
replaced with 4-oxocyclohexane carboxylic acid and
3-ethyl-N'-hydroxy-1H-indazole-1-carboximidamide, respectively.
[0477] LC-MS, m/z; 311 [M+H]+
Reference Example 060
Preparation of
3-[3-(3-ethyl-6-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]cyclobutanon-
e
##STR00062##
[0479] 3-Oxocyclobutanecarboxylic acid (2.48 g) was dissolved in
THF (36 ml). To the solution was added N,N'-carbonylimidazole (3.53
g), and the mixed solution was stirred at room temperature for 1
hour. To the reaction solution was added
3-ethyl-6-fluoro-N-hydroxy-1H-indazole-1-carboximidamide (4.03 g),
and the mixed solution was stirred at 50.degree. C. for 4 hours.
The reaction solution was cooled to room temperature and then
concentrated under reduced pressure, and water was added thereto.
The mixture was extracted with chloroform. The organic layer was
washed with brine, dried over sodium sulfate and filtered, and the
filtrate was concentrated under reduced pressure to give a
quantitative amount of
3-ethyl-6-fluoro-N-{[(3-oxocyclobutyl)carbonyl]oxy}-1H-indazole-1-carboxi-
midamide. Then, the
3-ethyl-6-fluoro-N-{[(3-oxocyclobutyl)carbonyl]oxy}-1H-indazole-1-carboxi-
midamide (4.85 g) was dissolved in acetic acid (76 ml), and the
solution was stirred at 90.degree. C. for 6 hours. The reaction
solution was concentrated under reduced pressure, saturated sodium
carbonate aqueous solution was added thereto, and the mixture was
extracted with chloroform. The organic layer was washed with brine,
dried over sodium sulfate and filtered, and the filtrate was
concentrated under reduced pressure. The residue was purified by
silica-gel chromatography (developing solvent: hexane/ethyl
acetate) to give the title compound (2.69 g).
[0480] LC-MS, m/z; 301 [M+H]+
Reference Example 061
Preparation of
3-chloro-1-[5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl]-1H-indazole
hydrochloride
##STR00063##
[0482] (1) To triphosgene (355 mg) was added methylene chloride (3
ml). To the mixture were added dropwise 3-chloroindazole (458 mg)
and triethylamine (1.95 ml) dissolved in methylene chloride (3 ml)
with stirring at 0.degree. C. The reaction solution was warmed to
room temperature, stirred for 30 minutes, and then cooled to
0.degree. C. again. To the reaction solution were added dropwise
tert-butyl 4-(hydrazinecarbonyl)piperidine-1-carboxylate (730 mg)
and triethylamine (0.63 ml) dissolved in methylene chloride (3 ml),
and the mixture was stirred at room temperature for 4 hours. To the
reaction solution was added saturated sodium carbonate aqueous
solution, and the resultant solution was extracted with chloroform.
The organic layer was dried over sodium sulfate and filtered, and
the filtrate was concentrated under reduced pressure. The residue
was purified by silica-gel chromatography (developing solvent:
chloroform/methanol=95/5) to give tert-butyl
4-({2-[(3-chloro-1H-indazol-1-yl)carbonyl]hydrazinyl}carbonyl)piperidine--
1-carboxylate (519 mg).
[0483] LC-MS, m/z; 422 [M+H]+
[0484] (2) The above-prepared compound (519 mg) was dissolved in
methylene chloride (12 ml). To the solution was added
triphenylphosphine (645 mg), carbon tetrachloride (0.24 ml) and
triethylamine (0.7 ml), and the mixed solution was refluxed
overnight. The reaction solution was cooled to room temperature and
concentrated under reduced pressure. The residue was purified by
silica-gel chromatography (developing solvent: hexane/ethyl
acetate
[0485] =3/1) to give tert-butyl
4-[5-(3-chloro-1H-indazol-1-yl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxy-
late (355 mg) as an oil.
[0486] LC-MS, m/z; 404 [M+H]+
[0487] (3) To the above-prepared compound (355 mg) was added 4 N
HCl/dioxane (10 ml) and methanol (5 ml), and the mixed solution was
stirred at room temperature for 5 hours. The reaction solution was
concentrated under reduced pressure. To the residue was added ethyl
acetate (10 ml), and the crystallized white solid was collected on
a filter to give the title compound (229 mg).
[0488] LC-MS, m/z; 304 [M+H]+
Reference Example 062
Preparation of
1-[3-(piperidin-4-yl)isoxazol-5-yl]-3-(propan-2-yl)-1H-indazole
hydrochloride
##STR00064##
[0490] (1) To 3-(propan-2-yl)-1H-indazole (801 mg), copper (II)
chloride (297 mg) and sodium carbonate (1.06 g) was added dropwise
pyridine (791 mg) in toluene (5 ml) under oxygen atmosphere, and
the mixture was stirred at 70.degree. C. for 30 minutes. To the
mixture was added dropwise (triisopropylsilyl)acetylene (912 mg) in
toluene (5 ml), and the mixture was stirred at 70.degree. C. for 4
hours. The reaction solution was concentrated under reduced
pressure, and the residue was purified by silica-gel chromatography
(developing solvent: hexane/ethyl acetate=7:3) to give
3-(propan-2-yl)-1-[(tripropan-2-ylsilyl)ethynyl]-1H-indazole (260
mg) as a colorless oil.
[0491] (2) The above-prepared compound (260 mg) was dissolved in
tetrahydrofuran (14 ml). To the solution was added 1N
tetrabutylammonium fluoride/tetrahydrofuran solution (0.9 ml), and
the mixed solution was stirred at room temperature for 1 hour. The
reaction solution was concentrated under reduced pressure, and the
residue was purified by silica-gel chromatography (developing
solvent: hexane/ethyl acetate=7:3) to give
1-ethynyl-3-(propan-2-yl)-1H-indazole (82 mg) as a colorless
oil.
[0492] LC-MS, m/z; 185 [M+H]+
[0493] (3) Text-butyl
4-[(hydroxylimino)methyl]piperidine-1-carboxylate (2.59 g) was
dissolved in DMF (25 ml). To the solution was added
N-chlorosuccinimide (1.47 g), and the mixture was stirred at room
temperature for 2 hours and then water (40 ml) was slowly added
dropwise thereto with stirring. The crystallized solid was
collected on a filter and washed with water. The resultant solid
was dried under reduced pressure at 50.degree. C. to give
tert-butyl [chloro(hydroxylimino)methyl]piperidine-1-carboxylate
(2.31 g) as a white crystal.
[0494] (4) 1-Ethynyl-3-(propan-2-yl)-1H-indazole (82 mg),
tert-butyl 4-[chloro(hydroxylimino)methyl]piperidine-1-carboxylate
(117 mg) and sodium bicarbonate (243 mg) were suspended in toluene
(5 ml), and the suspension was stirred at room temperature
overnight. To the reaction solution was added water. The resultant
solution was extracted with ethyl acetate. The organic layer was
washed with brine, dried over sodium sulfate and filtered, and the
filtrate was concentrated under reduced pressure. The residue was
purified by silica-gel chromatography (developing solvent:
hexane/ethyl acetate=7:3) to give tert-butyl
4-{5-[3-(propan-2-yl)-1H-indazol-1-yl]isoxazol-3-yl}piperidine-1-carboxyl-
ate (100 mg) as a white solid.
[0495] LC-MS, m/z; 411 [M+H]+
[0496] (5) Tert-butyl
4-{5-[3-(propan-2-yl)-1H-indazol-1-yl]isoxazol-3-yl}piperidine-1-carboxyl-
ate (100 mg) was dissolved in dichloromethane (3 ml). To the
solution was added trifluoroacetic acid (3 ml) at 0.degree. C. with
stirring, and then the mixture was reacted at room temperature for
3 hours. The reaction solution was concentrated under reduced
pressure, toluene (5 ml) was added thereto, and the solution was
concentrated under reduced pressure (.times.3). To the residue was
added ethyl acetate to precipitate a crystal, and the resultant was
concentrated under reduced pressure to give the title compound (130
mg) as a colorless crystal.
Reference Example 063
Preparation of
3-chloro-1-[3-(piperidin-4-yl)-1,2,4-oxadiazol-5-yl]-1H-indazole
hydrochloride
##STR00065##
[0498] (1) 3-Chloro-1H-indazole-1-carbonitrile (355 mg), tert-butyl
4-[chloro(hydroxylimino)methyl]piperidine-1-carboxylate (525 mg)
and sodium bicarbonate (672 mg) were suspended in toluene (10 ml),
and the suspension was stirred at 60.degree. C. overnight. The
reaction solution was cooled, and water was added thereto. The
mixture was extracted with ethyl acetate. The organic layer was
dried over sodium sulfate and filtered, and the filtrate was
concentrated under reduced pressure. The residue was purified by
silica-gel chromatography (developing solvent: hexane/ethyl
acetate=4:1) to give tert-butyl
4-[5-(3-chloro-1H-indazol-1-yl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxy-
late (605 mg).
[0499] LC-MS, m/z; 404 [M+H]+
[0500] (2) To the above-prepared compound (605 mg) were added 4 N
HCl/dioxane (15 ml) and methanol (2 ml), and the mixture was
stirred at room temperature for 3 hours. The reaction solution was
concentrated under reduced pressure, and the crystallized white
solid was collected on a filter to give the title compound (360
mg).
[0501] LC-MS, m/z; 304 [M+H]+
Reference Example 064
Preparation of
1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine
trifluoroacetate
##STR00066##
[0503] (1) 1H-Pyrrolo[2,3-b]pyridine (1.54 g) was dissolved in
dichloromethane (130 ml). To the solution were added triethylamine
(3.6 ml), N,N-dimethyl-4-aminopyridine (0.53 g) and cyanogen
bromide (4.13 g), and the mixture was stirred at room temperature
for 3 hours. To the reaction solution was added water. The
resultant solution was extracted with dichloromethane. The organic
layer was washed with water and brine, dried over sodium sulfate,
and filtered. The filtrate was concentrated under reduced pressure.
The residue was purified by silica-gel chromatography (developing
solvent: hexane/ethyl acetate) to give
1H-pyrrolo[2,3-b]pyridine-1-carbonitrile (2.12 g).
[0504] LC-MS, m/z; 144 [M+H].sup.+.
[0505] (2) The above-prepared compound (1.98 g) was dissolved in a
mixed solvent of ethanol (68 ml) and water (14 ml). To the solution
was added hydroxylamine hydrochloride (2.88 g) and potassium
carbonate (3.06 g), and the mixture was refluxed. The reaction
solution was cooled to room temperature and then concentrated under
reduced pressure, water was added thereto, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
brine, dried over sodium sulfate and filtered, and the filtrate was
concentrated under reduced pressure to give
N-hydroxy-1,1-pyrrolo[2,3-b]pyridine-1-carboximidamide (1.23
g).
[0506] LC-MS, m/z; 177 [M+H]+
[0507] (3) The above-prepared compound (1.03 g) was dissolved in
DMF (28 ml). To the solution was added 60% sodium hydride (269 mg)
at ice temperature, and the mixture was stirred for 1 hour. To the
reaction solution was added 1-tert-butyl 4-ethyl
piperidine-1,4-dicarboxylate (1.50 g) in DMF (8.5 ml), and the
mixture was further stirred at room temperature for 3 hours. To the
reaction solution was added water, and the crystallized precipitate
was collected on a filter to give tert-butyl
4-[3-(1H-pyrrolo[2,3-b]pyridin-1-yl)-1,2,4-oxadiazol-5-yl]piperidine-1-ca-
rboxylate (1.10 g).
[0508] LC-MS, m/z; 370 [M+H].sup.+.
[0509] (4) The above-prepared compound (1.10 g) was dissolved in
dichloromethane (22 ml). To the solution was added trifluoroacetic
acid (2.2 ml), and the mixed solution was stirred at room
temperature overnight. The reaction solution was concentrated under
reduced pressure to give a quantitative amount of the title
compound.
[0510] LC-MS, m/z; 270 [M+H]+
Reference Example 065
Preparation of
1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-6-(propan-2-yl)-1H-pyrrolo[2,-
3-b]pyridine hydrochloride
##STR00067##
[0512] (1) 6-Isopropyl-1H-pyrrolo[2,3-b]pyridine (239 mg) was
dissolved in dichloromethane (15 ml). To the solution were added
triethylamine (0.42 ml), N,N-dimethyl-4-aminopyridine (61 mg) and
cyanogen bromide (474 mg), and the mixture was stirred at room
temperature for 24 hours. To the reaction solution was added water,
and the resultant solution was extracted with dichloromethane. The
organic layer was washed with water and brine, dried over sodium
sulfate and filtered, and the filtrate was concentrated under
reduced pressure. The residue was purified by silica-gel
chromatography (developing solvent: hexane ethyl acetate) to give
6-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carbonitrile (128
mg).
[0513] LC-MS, m/z; 186 [M+H]+
[0514] (2) The above-prepared compound (128 mg) was dissolved in a
mixed solvent of THF (3.5 ml) and water (0.35 ml). To the solution
were added hydroxylamine hydrochloride (62 mg) and triethylamine
(0.19 ml), and the mixture was refluxed for 2 hours. The reaction
solution was cooled to room temperature, water was added thereto,
and the resultant solution was extracted with ethyl acetate. The
organic layer was washed with brine, dried over sodium sulfate and
filtered, and the filtrate was concentrated under reduced pressure
to give a quantitative amount of
N-hydroxy-6-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboximidamide.
[0515] LC-MS, m/z; 219 [M+H]+
[0516] (3) 1-(Tert-butoxycarbonyl)piperidine-4-carboxylic acid (181
mg) was dissolved in DMF (1.4 ml). To the solution was added
N,N'-carbonylimidazole (128 mg), and the mixture was stirred at
room temperature for 1 hour. To the reaction solution was added the
above-prepared compound (157 mg) in DMF (1.4 ml), and the mixture
was stirred at 120.degree. C. for 12 hours. The reaction solution
was cooled to room temperature, water was added thereto, and the
resultant solution was extracted with ethyl acetate. The organic
layer was washed with water several times, dried over sodium
sulfate and filtered, and the filtrate was concentrated under
reduced pressure to give tert-butyl
4-{3-[6-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl]-1,2,4-oxadiazol-5-yl-
}piperidine-1-carboxylate (278 mg).
[0517] LC-MS, m/z; 412 [M+H]+
[0518] (4) To the above-prepared compound (278 mg) was added 4
NHCl/1,4-dioxane (14 ml), and the mixture was stirred at room
temperature for 4 hours. The reaction solution was concentrated
under reduced pressure to give a quantitative amount of the title
compound.
[0519] LC-MS, m/z; 312 [M+H]+
Reference Example 066
Preparation of 2-(tetrahydrofuran-2-yl)ethanol
##STR00068##
[0521] Lithium aluminum hydride (4.20 g) was stirred in THF (100
ml) under nitrogen atmosphere at -40.degree. C. To the mixture was
slowly added dropwise ethyl tetrahydrofuran-2-acetate (7.0 g) in
THF (63 ml). After the dropping, the mixture was stirred at
-40.degree. C. for 1.5 hours. After confirming the completion of
the reaction, sodium fluoride (18.6 g) and water (8.0 ml) were
added thereto, and the mixture was stirred. The reaction solution
was filtered through Celite, and the resultant solution was
evaporated under reduced pressure to give 2-(tetrahydrofuran-2-yl)
ethanol (4.40 g) as a colorless oil.
[0522] LC-MS, m/z; 117 [M+H]+
Reference Example 067
Preparation of 2-(tetrahydrofuran-2-yl)ethyl 4
methylbenzenesulfonate
##STR00069##
[0524] To 2-(tetrahydrofuran-2-yl)ethanol (4.40 g) in
dichloromethane (160 ml) were added triethylamine (10.6 ml),
trimethylamine hydrochloride (0.362 g) and p-toluenesulfonic acid
chloride (7.94 g), and the mixture was stirred at 0.degree. C.
After the reaction was completed, water was added to the reaction
solution. The mixture was extracted with chloroform, the organic
layer was dried over sodium sulfate and filtered, and the filtrate
was concentrated under reduced pressure to give
2-(tetrahydrofuran-2-yl)ethyl 4-methylbenzenesulfonate (10.19 g) as
a colorless oil.
[0525] LC-MS, m/z; 271 [M+H]+
Reference Example 068
Preparation of 2-(tetrahydropyran-2-yl)ethyl
4-methylbenzenesulfonate
##STR00070##
[0527] 2-(2-Hydroxyethyl)-tetrahydropyrane (0.50 g) was reacted
with p-toluenesulfonic acid chloride (0.805 g) in the same manner
as in Reference Example 067 to give 2-(tetrahydropyran-2-yl)ethyl
4-methylbenzenesulfonate (1.00 g) as a colorless oil.
[0528] LC-MS, m/z; 285 [M+H]+
Reference Example 069
Preparation of (tetrahydro-2H-pyran-3-yl)methyl
4-methylbenzenesulfonate
##STR00071##
[0530] (Tetrahydro-2H-pyran-3-yl)methanol (0.45 g) was reacted with
p-toluenesulfonic acid chloride (0.812 g) in the same manner as in
Reference Example 067 to give (tetrahydro-2H-pyran-3-yl)methyl
4-methylbenzenesulfonate (1.21 g) as a colorless oil.
[0531] LC-MS, m/z; 271 [M+H]+
Reference Example 070
Preparation of 2-(7-fluoro-1H-indazol-3-yl)propan-2-ol
##STR00072##
[0533] (1) 7-Fluoro-1H-indazole-3-carboxylic acid (8.0 g) was
dissolved in methanol (500 ml). To the solution was added
concentrated H.sub.2SO.sub.4 (15 ml) at ice temperature, and the
mixed solution was stirred under reflux for 7 hours. The solvent
was removed under reduced pressure, chloroform was added to the
residue, and the resultant was neutralized with saturated sodium
bicarbonate aqueous solution. The organic layer was further washed
with water, dried, and concentrated under reduced pressure. The
residue was purified by silica-gel chromatography (column;
Hi-Flash.TM. developing solvent: hexane/ethyl acetate) and then
purified again by silica-gel chromatography (column; Hi-Flash.TM.,
developing solvent: chloroform/methanol) to give methyl
7-fluoro-1H-indazole-3-carboxylate (4.15 g) as a white crystal.
[0534] (2) Methyl 7-fluoro-1H-indazole-3-carboxylate (2.4 g) was
dissolved in THF (70 ml), and the solution was cooled to
-70.degree. C. To the solution was added dropwise
CH.sub.3MgI/diethyl ether (2.0 M, 21.63 ml) under nitrogen
atmosphere.
[0535] The reaction solution was stirred overnight with heating at
50.degree. C. After the reaction was completed, saturated ammonium
chloride aqueous solution (100 ml) was added dropwise to the
mixture at ice temperature. The mixture was extracted with ethyl
acetate, the organic layer was further washed with brine, dried and
concentrated under reduced pressure, and the residue was purified
by silica-gel chromatography (column; Hi-Flash.TM., developing
solvent: hexane/ethyl acetate) to give the title compound (2.06 g)
as a white crystal.
[0536] LC-MS, m/z; 195 [M+H]+
Reference Example 071
Preparation of 2-fluoro-3-methoxyaniline hydrochloride
##STR00073##
[0538] (1) 2-Fluoro-3-methoxybenzoic acid (5.1 g), triethylamine
(5.06 ml) and diphenylphosphoryl azide (9.08 g) were added to
tert-butyl alcohol (100 ml), and the mixture was refluxed
overnight. Then, the reaction solution was cooled and concentrated
under reduced pressure, and the residue was purified by silica-gel
chromatography (column; Hi-Flash.TM., developing solvent:
hexane/ethyl acetate 10:1) to give tert-butyl
(2-fluoro-3-methoxyphenyl)carbamate (5.28 g) as a colorless
solid.
[0539] (2) Tert-butyl (2-fluoro-3-methoxyphenyl)carbamate (5.28 g)
was dissolved in 4N HCl/dioxane (30 ml), and the solution was
stirred at room temperature for 3 hours. Then, the reaction
solution was evaporated under reduced pressure, toluene (100 ml)
was added thereto, the mixture was evaporated again under reduced
pressure, and the residue was dried under reduced pressure to give
the title compound (3.89 g) as a white solid.
[0540] LC-MS, m/z; 142 [M+H]+
Reference Example 072
Preparation of 2-fluoro-5-methoxyaniline hydrochloride
##STR00074##
[0542] (1) 4-Fluoro-3-nitrophenol (3.14 g) was dissolved in acetone
(40 ml). To the solution were added methyl iodide (5.68 g) and
potassium carbonate (5.53 g), and the mixture was stirred at
40.degree. C. for 6 hours. Then, methylene chloride (50 ml) was
added thereto, the insoluble matter was removed by filtration, and
the filtrate was concentrated under reduced pressure. The residue
was dissolved in ethyl acetate (50 ml). The organic layer was
washed with 1N sodium hydroxide aqueous solution, water and brine,
dried over sodium sulfate, and filtered. The filtrate was
concentrated under reduced pressure to give
1-fluoro-4-methoxy-2-nitrobenzene (3.47 g) as a brown oil.
[0543] (2) 1-Fluoro-4-methoxy-2-nitrobenzene (3.47 g) was dissolved
in methanol (30 ml). To the solution was added 10% palladium/carbon
(2 g), and the mixed solution was stirred under hydrogen atmosphere
for 5 hours. The reaction solution was filtered through Celite, and
the filtrate was concentrated under reduced pressure. The residue
was dissolved in ethyl acetate (10 ml), and 4 N HCl/ethyl acetate
solution was added dropwise thereto. The resulting crystal was
collected on a filter, and dried to give the title compound (3.2 g)
as a brown solid.
[0544] LC-MS, m/z; 142 [M+H]+
[0545] The compounds in the following table (i.e. Reference
Examples 073 to 075) were prepared in the same manner as in
Reference Example 013 except that the aniline and
cyclopropylcyanide of (1) in Reference Example 013 were replaced
with the corresponding starting compound and isopropylcyanide,
respectively.
##STR00075##
TABLE-US-00006 TABLE 6 Ref. Compound Ex. R.sup.4 R.sup.6 R.sup.7
Name LC-MS, m/z 073 H MeO F 7-fluoro-6- LC-MS, m/z; 209 [M + H]+
methoxy-3- (propan-2-yl)- 1H-indazole 074 MeO H F 7-fluoro-4-
LC-MS, m/z; 209 [M + H]+ methoxy-3- (propan-2-yl)- 1H-indazole 075
H H Me 7-methyl-3- LC-MS, m/z; 175 [M + H]+ (propan-2-yl)-
1H-indazole
[0546] The compounds in the following table (i.e. Reference
Examples 076 to 084) were prepared in the same manner as in
Reference Example 001 except that the 2-aminobenzonitrile and the
isopropylmagnesium chloride were replaced with the corresponding
starting compound and Grignard reagent of R.sup.3MgX wherein X is
halogen atom, respectively.
##STR00076##
TABLE-US-00007 TABLE 7 Ref. Ex. R.sup.3 R.sup.4 R.sup.5 R.sup.6
R.sup.7 Compound Name LC-MS, m/z 076 .sup.iPr Cl H H H 4-chloro-3-
LC-MS, m/z; (propan-2-yl)- 195 [M + H]+ 1H-indazole 077 .sup.iPr Me
H H H 4-methyl-3- No data (propan-2-yl)- 1H-indazole 078 .sup.iPr H
Cl H H 5-chloro-3- LC-MS, m/z; (propan-2-yl)- 195 [M + H]+
1H-indazole 079 .sup.iPr H Me H H 5-methyl-3- LC-MS, m/z;
(propan-2-yl)- 175 [M + H]+ 1H-indazole 080 .sup.iPr H MeO H H
5-methoxy-3- LC-MS, m/z; (propan-2-yl)- 191 [M + H]+ 1H-indazole
081 .sup.iPr H H Cl H 6-chloro-3- LC-MS, m/z; (propan-2-yl)- 195 [M
+ H]+ 1H-indazole 082 .sup.iPr H H Me H 6-methyl-3- LC-MS, m/z;
(propan-2-yl)- 175 [M + H]+ 1H-indazole 083 Et H H Me H 3-ethyl-6-
LC-MS, m/z; methyl-1H- 161 [M + H]+ indazole 084 .sup.iPr H H H MeO
7-methoxy-3- LC-MS, m/z; (propan-2-yl)- 191 [M + H]+
1H-indazole
Reference Example 085
Preparation of 7-fluoro-3-(trifluoromethyl)-1H-indazole
##STR00077##
[0548] (1) 2,3-Difluorobenzaldehyde (711 mg) and
trifluoromethyltrimethylsilane (853 mg) were dissolved in THF (5.0
ml). To the solution was added dropwise tetra-n-butylammonium
fluoride (1M in THF, 75 .mu.l) at ice temperature, and the mixture
was stirred at room temperature for 2 hours. To the reaction
solution was further added 1.0 ml of tetra-n-butylammonium fluoride
(1M in THF), and the mixed solution was stirred at room temperature
for 30 minutes. To the reaction solution was added dilute HCl. The
mixture was extracted with ethyl acetate, the organic layer was
washed with water and brine, dried over anhydrous sodium sulfate,
and concentrated under reduced pressure to give a quantitative
amount of 1-(2,3-difluorophenyl)-2,2,2-trifluoroethanol.
[0549] (2) 1-(2,3-Difluorophenyl)-2,2,2-trifluoroethanol (1.06 g)
and manganese dioxide (4.35 g) were added to methylene chloride (32
ml), and the mixture was stirred at room temperature for 21 hours.
Then, the reaction mixture was filtered through Celite, and the
filtrate was concentrated under reduced pressure to give a
quantitative amount of
1-(2,3-difluorophenyl)-2,2,2-trifluoroethanone.
[0550] (3) 1-(2,3-Difluorophenyl)-2,2,2-trifluoroethanone (530 mg)
and hydrazine monohydrate (1.89 g) were added to 1,4-dioxane (5.3
ml), and the mixture was stirred at 100.degree. C. for 4 hours. To
the reaction solution was added water. The mixture was extracted
with ethyl acetate, and the organic layer was dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The residue
was purified by silica-gel chromatography (column; Hi-Flash.TM.,
developing solvent: hexane/ethyl acetate) to give the title
compound (253 mg).
[0551] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.14-7.29 (2H, m),
7.58-7.70 (1H, m), 11.04 (1H, br s).
[0552] The compounds in the following table (i.e. Reference
Examples 086 to 087) were prepared in the same manner as in
Reference Example 085 (3) by using an intermediate which is
prepared in the same manner as in Reference Example 001 except that
the 2-aminobenzonitrile and the isopropylmagnesium chloride were
replaced with 2,3,4-trifluoro benzonitrile and Grignard reagent
defined as R.sup.3MgX wherein X is halogen atom, respectively.
##STR00078##
TABLE-US-00008 TABLE 8 Ref. Ex. R.sup.3 Compound Name LC-MS, m/z
086 Et 3-ethyl-6,7-difluoro-1H- LC-MS, m/z; 183 [M + H]+ indazole
087 .sup.iPr 6,7-difluoro-3-(propan-2- LC-MS, m/z; 197 [M + H]+
yl)-1H-indazole
Reference Example 088
Preparation of 7-fluoro-3-(prop-1-en-2-yl)-1H-indazole
##STR00079##
[0554] (1) To a mixed solution of 7-fluoro-1H-indazole-3-carboxylic
acid (15.0 g) and tetrahydrofuran (600 ml) were added pyridine
(14.8 ml) and N,O-dimethylhydroxylamine (8.94 g) at ice
temperature. The mixture was stirred for 1 hour, warmed to room
temperature, and further stirred for 1 hour. To the reaction
solution were added pyridine (13.4 ml) and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (31.9
g), and the mixture was stirred at room temperature overnight.
After the reaction was completed, the solvent was evaporated under
reduced pressure. To the residue was added water (1.0 l), and the
resultant crystal was collected on a filter to give
7-fluoro-N-methoxy-N-methyl-1H-indazole-3-carboxamide (12.4 g) as a
yellow crystal.
[0555] (2) 7-Fluoro-N-methoxy-N-methyl-1H-indazole-3-carboxamide
(1.0 g) was dissolved in tetrahydrofuran (50 ml). To the solution
was added dropwise CH.sub.3MgI/THF (2.0 M, 6.72 ml) at ice
temperature, and the mixture was stirred at room temperature for 7
hours. The reaction solution was ice-cooled, quenched with
saturated ammonium chloride aqueous solution, and extracted with
ethyl acetate. The organic layer was washed with brine and dried,
and then the solvent was evaporated under reduced pressure to give
1-(7-fluoro-1H-indazol-3-yl)ethanone (800 mg).
[0556] (3) Methyltriphenylphosphonium iodide (7.90 g) was suspended
in THF (98 ml) at ice temperature. To the suspension was added
potassium tert-butoxide (2.19 g), and the mixture was stirred for
30 minutes. To the mixture was added dropwise
1-(7-fluoro-1H-indazol-3-yl)ethanone (1.16 g) in THF (17 ml), and
the resultant mixture was stirred at room temperature for 3 hours.
To the reaction mixture was added hexane (108 ml). The precipitate
was removed by filtration, and the filtrate was concentrated under
reduced pressure. The residue was purified by silica-gel
chromatography (column; Hi-Flash.TM., developing solvent:
hexane/ethyl acetate) to give the title compound (1.00 g).
[0557] LC-MS, m/z; 177 [M+H]+
Reference Example 089
Preparation of 3-pert-butyl-1H-indazole
##STR00080##
[0559] 2-(Trimethylsilyl)phenyl trifluoromethanesulfonate (1.79 g),
2,2-dimethylpropanal tosylhydrazone (1.27 g), benzyltriethyl
ammonium chloride (285 mg) and cesium fluoride (2.28 g) were
suspended in THF (125 ml), and the suspension was stirred at
70.degree. C. for 23 hours under nitrogen atmosphere. To the
reaction mixture was added water, and the mixture was extracted
with ethyl acetate. The organic layer was dried over anhydrous
sodium sulfate and concentrated under reduced pressure, and then
the residue was purified by amino silica-gel chromatography
(column; Hi-Flash.TM., developing solvent: hexane/ethyl acetate) to
give the title compound (413 mg).
[0560] LC-MS, m/z; 175 [M+H]+
Reference Example 090
Preparation of 7-fluoro-3-iodo-1H-indazole
##STR00081##
[0562] To 7-fluoro-1H-indazole (5 g) in N,N-dimethylformamide (50
ml) were added iodine (18.6 g) and potassium hydroxide (8.2 g), and
the mixture was stirred at 50.degree. C. for 20 minutes. To the
reaction solution was added 10% sodium bisulfite aqueous solution
at room temperature, and the mixture was stirred for 2 hours. The
resulting crystal was collected on a filter and dried to give the
title compound (8.2 g).
[0563] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.13-7.21 (2H, m),
7.28-7.35 (1H, m), 10.48 (1H, br s).
[0564] LC-MS, m/z; 263 [M+H]+
[0565] The compounds in the following table (i.e. Reference
Examples 091 to 109) were prepared in the same manner as in
Reference Example 016 except that the 3-ethyl-6-fluoro-1H-indazole
was replaced with the corresponding starting compound (which is
described in Reference Example 070 and Reference Examples 073 to
090).
##STR00082##
TABLE-US-00009 TABLE 9 Ref. Compound .sup.1H-NMR/ Ex. R.sup.3
R.sup.4 R.sup.5 R.sup.6 R.sup.7 Name LC-MS, m/z 091.sup.1)
##STR00083## H H H F 7-fluoro-N'- hydroxy-3-(2- hydroxypropan-
2-yl)-1H- indazole-1- carboximidamide LC-MS, m/z; 253 [M + H]+
092.sup.1) .sup.iPr H H MeO F 7-fluoro-N'- LC-MS, hydroxy-6- m/z;
267 methoxy-3- [M + H]+ (propan-2-yl)- 1H-indazole-1-
carboximidamide 093.sup.1) .sup.iPr MeO H H F 7-fluoro-N'- LC-MS,
hydroxy-4- m/z; 267 methoxy-3- [M + H]+ (propan-2-yl)-
1H-indazole-1- carboximidamide 094 .sup.iPr Cl H H H 4-chloro-N'-
LC-MS, hydroxy-3- m/z; 253 (propan-2-yl)- [M + H]+ 1H-indazole-1-
carboximidamide 095 .sup.iPr Me H H H N'-hydroxy-4- LC-MS,
methyl-3- m/z; 233 (propan-2-yl)- [M + H]+ 1H-indazole-1-
carboximidamide 096 .sup.iPr H Cl H H 5-chloro-N'- LC-MS,
hydroxy-3- m/z; 253 (propan-2-yl)- [M + H]+ 1H-indazole-1-
carboximidamide 097 .sup.iPr H Me H H N'-hydroxy-5- LC-MS,
methyl-3- m/z; 233 (propan-2-yl)- [M + H]+ 1H-indazole-1-
carboximidamide 098 .sup.iPr H MeO H H N'-hydroxy-5- LC-MS,
methoxy-3- m/z; 249 (propan-2-yl)- [M + H]+ 1H-indazole-1-
carboximidamide 099 .sup.iPr H H Cl H 6-chloro-N'- LC-MS,
hydroxy-3- m/z; 253 (propan-2-yl)- [M + H]+ 1H-indazole-1-
carboximidamide 100 .sup.iPr H H Me H N'-hydroxy-6- LC-MS,
methyl-3- m/z; 233 propan-2-yl)- [M + H]+ 1H-indazole-1-
carboximidamide 101 Et H H Me H 3-ethyl-N'- LC-MS, hydroxy-6- m/z;
219 methyl-1H- [M + H]+ indazole-1- carboximidamide 102 .sup.iPr H
H H Me N'-hydroxy-7- LC-MS, methyl-3- m/z; 233 (propan-2-yl)- [M +
H]+ 1H-indazole-1- carboximidamide 103.sup.3) .sup.iPr H H H MeO
N'-hydroxy-7- LC-MS, methoxy-3- m/z; 249 (propan-2-yl)- [M + H]+
1H-indazole-1- carboximidamide 104 Et H H F F 3-ethyl-6,7- LC-MS,
difluoro-N'- m/z; 219 hydroxy-1H- [M + H]+ indazole-1-
carboximidamide 105 .sup.iPr H H F F 6,7-difluoro- LC-MS,
N'-hydroxy-3- m/z; 255 (propan-2-yl)- [M + H]+ 1H-indazole-1-
carboximidamide 106.sup.1) ##STR00084## H H H F 7-fluoro-N'-
hydroxy-3- (prop-1-en-2- yl)-1H- indazole-1- carboximidamide LC-MS,
m/z; 235 [M + H]+ 107.sup.2) ##STR00085## H H H H 3-tert-butyl-
N'-hydroxy-1H- indazole-1- carboximidamide LC-MS, m/z; 233 [M + H]+
108.sup.2) ##STR00086## H H H F 7-fluoro-N'- hydroxy-3-
(trifluoromethyl)- 1H- indazole-1- carboximidamide LC-MS, m/z; 263
[M + H]+ 109.sup.2) I H H H F 7-fluoro-N'- .sup.1H-NMR hydroxy-3-
(DMSO-d.sub.6) iodo-1H- .delta.: 6.44 indazole-1- (2H, br
carboximidamide s), 7.25- 7.46 (3H, m), 9.73 (1H, s). LC-MS, m/z;
321 [M + H]+ .sup.1)In the process of the cyanation, potassium
tert-butoxide was used instead of the triethylamine and the
N,N-dimethyl-4-aminopyridine as a base, and THF was used instead of
the methylene chloride as a solvent. .sup.2)In the process of the
cyanation, cesium carbonate was used instead of the triethylamine
and the N,N-dimethyl-4-aminopyridine as a base, and DMF was used
instead of the methylene chloride as a solvent. .sup.3)In the
process of the cyanation, sodium hydride was used instead of the
triethylamine and the N,N-dimethyl-4-aminopyridine as a base, and
DMF was used instead of the methylene chloride as a solvent.
Reference Example 110
Preparation of
1-(tert-butoxycarbonyl)-2-methylpiperidine-4-carboxylic acid
##STR00087##
[0567] (1) 2-Methyl isonicotinate (733 mg) and concentrated
H.sub.2SO.sub.4 (70 mg) were dissolved in methanol (30 ml), and the
solution was refluxed for 20 hours. The reaction solution was
cooled and concentrated under reduced pressure. To the residue was
added saturated sodium bicarbonate aqueous solution, and the
mixture was extracted with chloroform. The organic layer was dried
over anhydrous sodium sulfate and concentrated under reduced
pressure to give methyl 2-methylpyridine-4-carboxylate (749
mg).
[0568] (2) To methanol (12 ml) were added methyl
2-methylpyridine-4-carboxylate (598 mg), di-tert-butyl dicarbonate
(1.73 g) and platinum (IV) oxide (60 mg). The mixture was stirred
under hydrogen atmosphere (45 psi) for days at room temperature.
The reaction mixture was filtered through Celite and concentrated
under reduced pressure, and the residue was purified by silica-gel
chromatography (column; Hi-Flash.TM., developing solvent:
hexane/ethyl acetate) to give 1-tert-butyl 4-methyl
2-methylpiperidine-1,4-dicarboxylate (401 mg).
[0569] (3) 1-Tert-butyl 4-methyl
2-methylpiperidine-1,4-dicarboxylate (377 mg) and sodium hydroxide
(180 mg) were dissolved in THF (6.6 ml), water (2.2 ml) and
methanol (2.2 ml). The mixture was stirred at room temperature for
2 hours. The reaction solution was adjusted to pH 2 by 2 N HCl, and
then THF and methanol were removed under reduced pressure. The
residue was extracted with methylene chloride, the organic layer
was dried over anhydrous sodium sulfate and concentrated under
reduced pressure to give the title compound (341 mg).
[0570] LC-MS, m/z; 244 [M+H]+
Reference Example 111
Preparation of
(3-endo)-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic
acid
##STR00088##
[0572] (1) Methyltriphenylphosphonium bromide (21.4 g) was
suspended in THF (180 ml). To the mixture was added dropwise
n-butyllithium (2.69 M in hexane, 22.3 ml) at ice temperature. The
reaction mixture was stirred at room temperature for 30 minutes. To
the mixture was added dropwise N-Boc-tropinone (3.62 g) in THF (9.0
ml) at ice temperature, and the mixture was further stirred at room
temperature for 20 hours. To the reaction mixture was added aqueous
saturated ammonium chloride (200 ml), and the resultant mixture was
quenched and extracted with ethyl acetate. Then, the organic layer
was dried over anhydrous sodium sulfate and concentrated under
reduced pressure.
[0573] The residue was purified by silica-gel chromatography
(column; Hi-Flash.TM., developing solvent: hexane/ethyl acetate) to
give tert-butyl
3-methylidene-8-azabicyclo[3.2.1]octane-8-carboxylate (1.95 g).
[0574] (2) Tert-butyl
3-methylidene-8-azabicyclo[3.2.1]octane-8-carboxylate (1.93 g) was
dissolved in THF (80 ml). To the solution was added dropwise
borane-tetrahydrofuran complex (1.0 M in THF, 10.4 ml) at ice
temperature, and the mixture was stirred at room temperature for 2
hours. To the reaction solution were added dropwise sodium
hydroxide aqueous solution (2N, 11.6 ml) and 30% hydrogen peroxide
water (4.7 ml) at ice temperature, and the mixture was further
stirred at room temperature for 3 hours. The reaction mixture was
quenched with 10% sodium bisulfite aqueous solution, THF was
removed under reduced pressure, and the mixture was extracted with
methylene chloride. The organic layer was dried over anhydrous
sodium sulfate, concentrated under reduced pressure, and the
residue was purified by silica-gel chromatography (column;
Hi-Flash.TM., developing solvent: hexane/acetone) to give
tert-butyl
3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.63
g).
[0575] (3) Tert-butyl
3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.60 g)
and sodium metaperiodate (6.51 g) were dissolved in acetonitrile
(6.0 ml), ethyl acetate (6.4 ml) and water (9.6 ml). To the
solution was added ruthenium (III) chloride monohydrate (86 mg),
and the mixture was stirred at room temperature for 1 hour. To the
reaction mixture was added water, and the mixture was extracted
with methylene chloride. The organic layer was washed with brine,
dried over anhydrous sodium sulfate, and concentrated under reduced
pressure. The residue was purified by silica-gel chromatography
(column; Hi-Flash.TM., developing solvent: hexane/acetone) to give
the title compound (1.18 g).
[0576] LC-MS, m/z; 256 [M+H]+
Reference Example 112
Preparation of
1'-(tert-butoxycarbonyl)-4'-methyl-1,4'-bipiperidine-4-carboxylic
acid
##STR00089##
[0578] (1) 1,4-Dioxa-8-azaspiro[4.5]decane (10 g) was dissolved in
toluene (50 ml). To the solution were added N-Boc-4-piperidone (8.4
g) and 1,2,3-triazole (2.93 ml). Then, a Dean-Stark trap was
attached to the reaction vessel, and the mixture was stirred under
reflux overnight. The reaction solution was ice-cooled,
CH.sub.3MgCl/THF (3.0 M, 56.21 ml) was added dropwise thereto, and
then mixture was warmed to room temperature and stirred for 2
hours. The reaction solution was ice-cooled, quenched with 20%
ammonium chloride aqueous solution, and extracted with ethyl
acetate. The organic layer was washed with 2 N sodium hydroxide
solution and water, dried over anhydrous sodium sulfate, and the
solvent was evaporated under reduced pressure. The residue was
purified by silica-gel chromatography (column; H-Flash.TM.,
developing solvent: hexane/ethyl acetate) to give tert-butyl
4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-4-methylpiperidine-1-carboxylate
(7.82 g) as a white crystal.
[0579] (2) Tert-butyl
4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-4-methylpiperidine-1-carboxylate
(6.5 g) and 6 N HCl (200 ml) were mixed, and the mixture was
stirred at room temperature overnight. The reaction solution was
ice-cooled, and alkalinized with sodium hydroxide. To the resultant
were added diethyl ether (100 ml) and Boc.sub.2O (5.0 g), and the
mixture was stirred at room temperature for 2 hours. After the
reaction was completed, the organic layer was washed with brine and
dried, and the solvent was evaporated under reduced pressure. The
residue was purified by silica-gel chromatography (column;
Hi-Flash.TM., developing solvent: hexane/ethyl acetate) to give
tert-butyl 4'-methyl-4-oxo-1,4'-bipiperidine-1'-carboxylate (4.1 g)
as a white crystal.
[0580] (3) Tert-butyl
4'-methyl-4-oxo-1,4'-bipiperidine-1'-carboxylate (500 mg) was
dissolved in THF. To the solution was added dropwise LiHMDS/THF
(1.09 M, 4.64 ml) with cooling at -78.degree. C. The mixture was
stirred for 1.5 hours with cooling at -78.degree. C. To the
reaction mixture was added dropwise N-phenyltrifluoromethanesulfone
imide (1.21 g) in THF (11 ml), and the mixture was stirred for 1
hour. The reaction mixture was warmed to -10.degree. C. over 2
hours and then to room temperature over 30 minutes, and then the
resultant was stirred for 1 hour. To the reaction solution was
added saturated sodium bicarbonate aqueous solution. The mixture
was extracted with ethyl acetate, the organic layer was washed with
brine and dried over anhydrous sodium sulfate, and the solvent was
evaporated under reduced pressure. The residue was purified by
silica-gel chromatography (column; Hi-Flash.TM., developing
solvent: hexane/ethyl acetate) to give tert-butyl
4-methyl-4-[4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridin-1(2H)-y-
l]piperidine-1-carboxylate (847 mg) as a white crystal.
[0581] (4) Tert-butyl
4-methyl-4-[4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridin-1
(2H)-yl]piperidine-1-carboxylate (847 mg) was dissolved in
dimethylformamide (20 ml). To the solution were added palladium
acetate (44 mg), triethylamine (551 .mu.l), triphenylphosphine (104
mg), and methanol (3.2 ml), and the mixture was stirred at room
temperature overnight under carbon monoxide atmosphere. To the
reaction solution was added water, and the mixture was extracted
with ethyl acetate. The organic layer was washed with water
(.times.3), dried, and the solvent was evaporated under reduced
pressure. The residue was purified by silica-gel chromatography
(column; Hi-Flash.TM., developing solvent: hexane/ethyl acetate) to
give methyl
1-[1-(tert-butoxycarbonyl)-4-methylpiperidin-4-yl]-1,2,3,6-tetrahydropyri-
dine-4-carboxylate (374 mg).
[0582] (5) Methyl
1-[1-(tert-butoxycarbonyl)-4-methylpiperidin-4-yl]-1,2,3,6-tetrahydropyri-
dine-4-carboxylate (374 mg) was dissolved in methanol (30 ml). To
the solution was added palladium carbon (10%, 1 g) under nitrogen
atmosphere, and the mixture was stirred overnight at ordinary
temperature and medium pressure (3.6 atm) under hydrogen
atmosphere. After the reaction was completed, palladium carbon was
removed by Celite filtration, the filtrate was evaporated under
reduced pressure to give 1'-tert-butyl 4-methyl
4'-methyl-1,4'-bipiperidine-1',4-dicarboxylate (368 mg).
[0583] (6) 1'-Teri-butyl 4-methyl
4'-methyl-1,4'-bipiperidine-1',4-dicarboxylate (368 mg) was
dissolved in a mixed solvent of methanol (10 ml) and water (15 ml).
To the solution was added barium hydroxide (463 mg), and the mixed
solution was stirred at room temperature for 1 hour. After the
reaction was completed, methanol was removed under reduced
pressure, and CO.sub.2 gas was blown into the residue, and the
insoluble matter was removed by Celite filtration. The solid on the
filter paper was washed with water and ethanol, combined with the
filtrate, and the mixture was concentrated under reduced pressure
to give the TITLE COMPOUND (355 MG).
[0584] LC-MS, m/z; 327 [M+H]+
Reference Example 113
Preparation of
1'-(tert-butoxycarbonyl)-3',3'-dimethyl-1,4'-bipiperidine-4-carboxylic
acid
##STR00090##
[0586] (1) N-Boc-4-piperidone (10.0 g) was dissolved in THF (200
ml). To the solution was added sodium hydride (60 in oil, 4.22 g)
and methyl iodide (7.81 ml) at ice temperature, and the mixed
solution was stirred for 1 hour. The reaction solution was warmed
to room temperature over 2 hours, and then was further stirred at
room temperature for 1 hour. After the reaction was completed, the
reaction solution was ice-cooled, quenched with saturated ammonium
chloride aqueous solution, and extracted with ethyl acetate. The
organic layer was washed with brine and dried, and the solvent was
removed out under reduced pressure. The residue was purified by
silica-gel chromatography (column; Hi-Flash.TM., developing
solvent: hexane/ethyl acetate) to give tert-butyl
3,3-dimethyl-4-oxopiperidine-1-carboxylate (5.48 g) as a white
crystal.
[0587] (2) Tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate
(500 mg) was dissolved in THF (5.0 ml). To the solution was added
dropwise LiHMDS/THF (1.09 M, 2.22 ml) with cooling at -78.degree.
C., and the mixture was stirred for 1 hour. To the reaction mixture
was added dropwise N-phenyltrifluoromethanesulfone imide (0.86 g)
in THF (3.0 ml), and the mixture was further stirred for 1 hour.
The reaction mixture was warmed to 0.degree. C. over 1 hour and
then to room temperature, and stirred overnight. After the reaction
was completed, saturated ammonium chloride aqueous solution (10 ml)
and brine (20 ml) was added thereto. The mixture was stirred and
extracted with dichloromethane, the organic layer was dried, and
the solvent was removed out under reduced pressure. The residue was
purified by silica-gel chromatography (column; Hi-Flash.TM.,
developing solvent: hexane/ethyl acetate) to give tert-butyl
3,3-dimethyl-4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1
(2H)-carboxylate (523 mg) as a white crystal.
[0588] (3) To an eggplant flask were added palladium acetate (281
mg) and BINAP (1.17 g), the mixture was replaced with nitrogen, and
then tert-butyl
3,3-dimethyl-4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1
(2H)-carboxylate (4.51 g), ethyl isonipecotate (3.95 g), and
toluene (25 ml) were added thereto. To the mixed solution was added
potassium tert-butoxide (2.82 g), and the mixture was stirred at
80.degree. C. overnight. The reaction solution was cooled to room
temperature, and diluted with diethyl ether. The insoluble matter
was removed by filtration, the filtrate was removed out under
reduced pressure, and the residue was dissolved in dichloroethane.
To the solution were added sodium tri(acetoxy)borohydride (5.32 g)
and acetic acid (718 .mu.l), and the mixed solution was stirred at
room temperature for 5 hours. After the reaction was completed, the
mixture was quenched with water, and extracted with ethyl acetate.
The organic layer was washed with water and dried over anhydrous
sodium sulfate, and the solvent was evaporated under reduced
pressure. The residue was purified by silica-gel chromatography
(column; Hi-Flash.TM., developing solvent: hexane/ethyl acetate) to
give l'-tert-butyl 4-ethyl
3',3'-dimethyl-1,4'-bipiperidine-1',4-dicarboxylate (864 mg).
[0589] (4) 1'-Tert-butyl 4-ethyl
3',3'-dimethyl-1,4'-bipiperidine-1',4-dicarboxylate (864 mg) was
dissolved in a mixed solvent of methanol (20 ml) and water (30 ml).
To the solution was added barium hydroxide (1.04 g), and the
mixture was stirred at 50.degree. C. for 5 hours. After the
reaction was completed, methanol was removed under reduced
pressure, CO.sub.2 gas was blown into the residue, and the
insoluble matter was removed by Celite filtration. The solid on the
filter paper was washed with water and ethanol, combined with the
filtrate, and concentrated under reduced pressure to give the title
compound (977 mg).
[0590] LC-MS, m/z; 341 [M+H]+
Reference Example 114
Preparation of tert-butyl
8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate
##STR00091##
[0592] (1) To a mixed solution of paraformaldehyde (46.7 g),
methanol (150 ml) and potassium carbonate (64.5 g) was added
dropwise benzylamine (51 ml) over 1.5 hours, and the mixture was
stirred at room temperature for 2 days. The insoluble matter was
removed by Celite filtration, the solid on the filter paper was
washed with methanol, and the combined filtrate was evaporated
under reduced pressure. To the residue was added dichloromethane to
suspend the resultant. The insoluble matter in the suspension was
removed again by filtration. The filtrate was removed out under
reduced pressure and the resultant was purified by distillation
(102.degree. C. to 103.degree. C./1 mmHg) to give
N-benzyl-1-methoxy-N-(methoxymethyl)methanamine (56.2 g) as a
colorless oil.
[0593] (2) To a mixed solution of
N-benzyl-1-methoxy-N-(methoxymethyl)methanamine (23.2 g),
cyclopentanone (5.0 g) and acetonitrile (65 ml) was added
trimethylsilyl chloride (15.2 ml). The mixture was stirred at
50.degree. C. for 3 hours, and then stirred at room temperature for
2 days. After the reaction was completed, the mixture was quenched
with saturated sodium bicarbonate aqueous solution and extracted
with ethyl acetate. Then, the organic layer was dried over
anhydrous sodium sulfate, the solvent was removed under reduced
pressure, trifluoroacetic acid (20 ml) was added to the residue,
and the resultant was stirred at room temperature overnight. Then,
the trifluoroacetic acid was removed under reduced pressure, the
residue was dissolved in ethyl acetate, and the solution was washed
with saturated sodium bicarbonate aqueous solution and brine. The
organic layer was dried over anhydrous sodium sulfate, the solvent
was removed under reduced pressure, and the residue was purified by
silica-gel chromatography (column; Hi-Flash.TM., developing
solvent: hexane/ethyl acetate) to give
3-benzyl-3-azabicyclo[3.2.1]octan-8-one (1.42 g).
[0594] (3) 3-Benzyl-3-azabicyclo[3.2.1]octan-8-one (1.42 g) was
dissolved in ethyl acetate (30 ml). To the solution were added
Boc.sub.2O (2.88 g) and palladium hydroxide (185 mg), and the
mixture was stirred overnight at ordinary temperature and medium
pressure (3.6 atm). The palladium hydroxide was removed by Celite
filtration, the filtrate was concentrated under reduced pressure,
and the residue was purified by silica-gel chromatography (column;
Hi-Flash.TM., developing solvent: hexane/ethyl acetate) to give the
title compound (846 mg) as a white crystal.
[0595] LC-MS, m/z; 226 [M+H]+
Reference Example 115
Preparation of tert-butyl
9-oxo-3-azabicyclo[3.3.1]nonane-3-carboxylate
##STR00092##
[0597] The title compound was prepared in the same manner as in
Reference Example 114 except that the cyclopentanone was replaced
with cyclohexanone.
[0598] LC-MS, m/z; 240 [M+H]+
[0599] The compounds in the following table (i.e. Reference
Examples 116 to 127) were prepared in the same manner as in
Reference Example 033 or Reference Example 044 except that the
3-ethyl-6-fluoro-N'-hydroxy-1H-indazole-1-carboximidamide of
Reference Example 033 or the
N'-hydroxy-3-(propan-2-yl)-1H-indazole-1-carboximidamide of
Reference Example 044 was replaced with the corresponding starting
compound (which is described in Reference Examples 091 to 109).
##STR00093##
TABLE-US-00010 TABLE 10 Ref. Ex. R.sup.3 R.sup.4 R.sup.5 R.sup.6
R.sup.7 Compound Name LC-MS, m/z 116.sup.1) .sup.iPr Me H H H
tert-butyl 4-{3- LC-MS, m/z; [4-methyl-3- 426 [M + H]+
(propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}piperidine-1- carboxylate 117.sup.2) .sup.iPr Cl H H H
tert-butyl 4-{3- LC-MS, m/z; [4-chloro-3- 468 [M + Na]+
(propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}piperidine-1- carboxylate 118.sup.1) .sup.iPr H Me H H
tert-butyl 4-{3- LC-MS, m/z; [5-methyl-3- 448 [M + Na]+
(propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}piperidine-1- carboxylate 119.sup.2) .sup.iPr H Cl H H
tert-butyl 4-{3- No data [5-chloro-3- (propan-2-yl)-1H-
indazol-1-yl]- 1,2,4-oxadiazol-5- yl}piperidine-1- carboxylate
120.sup.2) .sup.iPr H MeO H H tert-butyl 4-{3- LC-MS, m/z;
[5-methoxy-3- 464 [M + Na]+ (propan-2-yl)-1H- indazol-1-yl]-
1,2,4-oxadiazol-5- yl}piperidine-1- carboxylate 121.sup.1) Et H H
Me H tert-butyl 4-[3- LC-MS, m/z; (3-ethyl-6-methyl- 434 [M + Na]+
1H-indazol-1-yl)- 1,2,4-oxadiazol-5- yl]piperidine-1- carboxylate
122.sup.1) .sup.iPr H H Me H tert-butyl 4-{3- LC-MS, m/z;
[6-methyl-3- 448 [M + Na]+ (propan-2-yl)-1H- indazol-1-yl]-
1,2,4-oxadiazol-5- yl}piperidine-1- carboxylate 123.sup.1) .sup.iPr
H H Cl H tert-butyl 4-{3- LC-MS, m/z; [6-chloro-3- 468 [M + Na]+
(propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}piperidine-1- carboxylate 124.sup.1) .sup.iPr H H H Me
tert-butyl 4-{3- LC-MS, m/z; [7-methyl-3- 426 [M + H]+
(propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}piperidine-1- carboxylate 125.sup.1) .sup.iPr H H H MeO
tert-butyl 4-{3- LC-MS, m/z; [7-methoxy-3- 442 [M + H]+
(propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}piperidine-1- carboxylate 126.sup.1) Et H H F F tert-butyl 4-[3-
LC-MS, m/z; (3-ethyl-6,7- 456 [M + Na]+ difluoro-1H- indazol-1-yl)-
1,2,4-oxadiazol-5- yl]piperidine-1- carboxylate 127.sup.1) .sup.iPr
H H F F tert-butyl 4-{3- LC-MS, m/z; [6,7-difluoro-3- 470 [M + Na]+
(propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}piperidine-1- carboxylate .sup.1)Prepared in the same manner as
in Reference Example 044. .sup.2)Prepared in the same manner as in
Reference Example 033.
[0600] The compounds in the following table (i.e. Reference
Examples 128 to 137) were prepared in the same manner as in
Reference Example 033 or Reference Example 044 except that the
3-ethyl-6-fluoro-N'-hydroxy-1H-indazole-1-carboximidamide of
Reference Example 033 or the
N'-hydroxy-3-(propan-2-yl)-1H-indazole-1-carboximidamide of
Reference Example 044 was replaced with the corresponding starting
compound.
##STR00094##
[0601] Wherein (B-2) means each cyclic amino structure shown in the
following table; and the Boc group is attached to the nitrogen atom
in the cyclic amine of (B-2).
TABLE-US-00011 TABLE 11 Ref. Compound .sup.1H-NMR/LC-MS, Ex.
R.sup.3 R.sup.6 R.sup.7 (B-2) Name m/z 128.sup.1) .sup.iPr H F
##STR00095## tert-butyl 3-{3-[7- fluoro-3-(propan-2-
yl)-1H-indazol-1- yl]-1,2,4- oxadiazol-5- yl}pyrrolidine-1-
carboxylate LC-MS, m/z; 438 [M + Na]+ 129.sup.2) .sup.iPr H F
##STR00096## tert-butyl 4-{3-[7- fluoro-3-(propan-2-
yl)-1H-indazol-1- yl]-1,2,4- oxadiazol-5-y}-4- hydroxypiperidine-
1-carboxylate LC-MS, m/z; 446 [M + H]+ 130.sup.3) .sup.iPr H F
##STR00097## tert-butyl 3-{3-[7- fluoro-3-(propan-2-
yl)-1H-indazol-1- yl]-1,2,4- oxadiazol-5-yl}-8- azabicyclo[3.2.1]
octane-8-carboxylate LC-MS, m/z; 456 [M + H]+ 131.sup.2) .sup.iPr H
F ##STR00098## tert-butyl 4-{3-[7- fluoro-3-(propan-2-
yl)-1H-indazol-1- yl]-1,2,4- oxadiazol-5-yl}-2- methylpiperidine-1-
carboxylate LC-MS, m/z; 444 [M + H]+ 132.sup.2) .sup.iPr H F
##STR00099## tert-butyl 3-({3- [7-fluoro-3- (propan-2-yl)-1H-
indazol-1-yl]- 1,2,4-oxadiazol-5- yl}methyl)azetidine-
1-carboxylate LC-MS, m/z; 416 [M + H]+ 133.sup.2) .sup.iPr H F
##STR00100## tert-butyl 4-({3- [7-fluoro-3- (propan-2-yl)-1H-
indazol-1-yl]- 1,2,4-oxadiazol-5- yl}methyl)piperidine-
1-carboxylate TLC Rf = 0.50 (hexane/EtOAc = 2/1) 134.sup.2)
.sup.iPr H F ##STR00101## tert-butyl (3R)-3- ({3-[7-fluoro-3-
(propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}methyl)pyrrolidine- 1-carboxylate LC-MS, m/z; 430 [M + H]+
135.sup.2) .sup.iPr H F ##STR00102## tert-butyl (3S)-3-
({3-[7-fluoro-3- (propan-2-yl)-1H- indazol-1-yl]-
1,2,4-oxadiazol-5- yl}methyl)pyrrolidine- 1-carboxylate LC-MS, m/z;
430 [M + H]+ 136.sup.2) Et H F tert-butyl (3S)-3- TLC Rf = 0.14
{[3-(3-ethyl-7- (hexane/EtOAc = fluoro-1H-indazol- 4/1)
1-yl)-1,2,4- oxadiazol-5- yl]methyl}pyrrolidine- 1-carboxylate
137.sup.2) .sup.iPr F H tert-butyl (3S)-3- TLC Rf = 0.17
({3-[6-fluoro-3- (hexane/EtOAc = (propan-2-yl)-1H- 4/1)
indazol-1-yl]- 1,2,4-oxadiazol-5- yl}methyl)pyrrolidine-
1-carboxylate .sup.1)Prepared in the same manner as in Reference
Example 044. .sup.2)Prepared in the same manner as in Reference
Example 033. .sup.3)Prepared by treating isopropyl chloroformate as
a condensing agent, and then using the same process as in Reference
Example 60.
Reference Example 138
Preparation of
cis-3-{[(2-nitrophenyl)sulfonyl]amino}cyclobutanecarboxylic
acid
##STR00103##
[0603] (1) To ethyl cis-3-aminocyclobutanecarboxylate (5 g,
prepared according to the method described in WO 2009/060278) and
triethylamine (1 ml) in dichloromethane (20 ml) was gradually added
2-nitrobenzenesulfonyl chloride (6.8 g), and the mixture was
stirred at room temperature for 1 hour. To the reaction solution
was added water (20 ml), and the resultant was extracted with
dichloromethane (10 ml, .times.2). The organic layer was dried over
anhydrous magnesium sulfate and filtered, the filtrate was removed
under reduced pressure, and the resultant was recrystallized from a
mixture of hexane and ethyl acetate to give ethyl
cis-3-{([2-(nitrophenyl)sulfonyl]amino}cyclobutanecarboxylate (8
g).
[0604] (2) To ethyl
cis-3-{[2-(nitrophenyl)sulfonyl]amino}cyclobutanecarboxylate (5 g)
in ethanol (30 ml) was added 2 mol/L sodium hydroxide (20 ml), and
the mixture was stirred at room temperature for 3 hours. The
reaction solution was adjusted to pH 2 by adding 1 mol/L HCl, and
ethanol was removed under reduced pressure. The precipitated solid
was collected on a filter, washed with water, and dried under
reduced pressure to give the title compound (4.6 g).
[0605] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.98-2.10 (2H, m),
2.15-2.27 (2H, m), 2.55-2.69 (1H, m), 3.58-3.74 (1H, m), 7.80-7.90
(2H, m), 7.91-8.01 (2H, m), 8.50 (1H, d, J=8.8 Hz), 12.15 (1H,
s).
Reference Example 139
Preparation of
3-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}cycl-
obutanone
##STR00104##
[0607] The title compound was prepared in the same manner as in
Reference Example 060 except that the
3-ethyl-6-fluoro-N-hydroxy-1H-indazole-1-carboximidamide was
replaced with
7-fluoro-N'-hydroxy-3-(propan-2-yl)-1H-indazole-1-carboximidamide.
[0608] LC-MS, m/z; 315 [M+H]+
Reference Example 140
Preparation of
4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}cycl-
ohexanone
##STR00105##
[0610] The title compound was prepared in the same manner as in
Reference Example 060 except that the
3-ethyl-6-fluoro-N-hydroxy-1H-indazole-1-carboximidamide and
3-oxocyclobutanecarboxylic acid were replaced with
7-fluoro-N'-hydroxy-3-(propan-2-yl)-1H-indazole-1-carboximidamide
and 4-oxocyclohexane carboxylic acid, respectively.
Reference Example 141
Preparation of
7-fluoro-1-[1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl]-3-(propan-2-yl)-1H--
indazole trifluoroacetate
##STR00106##
[0612] (1) 7-Fluoro-3-isopropyl-1H-indazole (712 mg), sodium
carbonate (212 mg), pyridine (158 mg) and copper (II) chloride (59
mg) were suspended in toluene (5.0 ml). To the suspension was added
dropwise triisopropylsilylacetylene (182 mg) in toluene (5.0 ml) in
air at 70.degree. C. over 3.5 hours, and then the mixture was
stirred for 4 hours. The reaction mixture was concentrated under
reduced pressure and the residue was purified by silica-gel
chromatography (column; Hi-Flash.TM., developing solvent:
hexane/ethyl acetate) to give
7-fluoro-3-(propan-2-yl)-1-[(tripropan-2-ylsilyl)ethynyl]-1H-indazole
(53 mg).
[0613] (2)
7-Fluoro-3-(propan-2-yl)-1-[(tripropan-2-ylsilyl)ethynyl]-1H-in-
dazole (53 mg) was dissolved in THF (2.6 ml). To the solution was
added tetra-n-butylammonium fluoride (1M in THF, 0.18 ml), and the
mixed solution was stirred at room temperature for 30 minutes. The
reaction solution was concentrated under reduced pressure and the
residue was purified by silica-gel chromatography (column;
Hi-Flash.TM., developing solvent: hexane/ethyl acetate) to give
1-ethynyl-7-fluoro-3-isopropyl-1H-indazole (27 mg). Then, the
obtained 1-ethynyl-7-fluoro-3-isopropyl-1H-indazole (27 mg) was
mixed with tert-butyl 4-azidopiperidine-1-carboxylate (34 mg),
copper (1.4 mg), and copper sulfate pentahydrate (1.7 mg) in a
mixed solvent of tert-butylalcohol (1.4 ml) and water (1.4 ml). The
mixture was stirred at 110.degree. C. for 30 minutes under nitrogen
atmosphere. To the reaction mixture was added brine, and the
mixture was extracted with chloroform. The organic layer was dried
over anhydrous sodium sulfate and concentrated under reduced
pressure, and the residue was purified by silica-gel chromatography
(column; Hi-Flash.TM., developing solvent: hexane:acetone) to give
tert-butyl
4-{4-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1H-1,2,3-triazol-1-yl}pip-
eridine-1-carboxylate (48 mg).
[0614] (3) Tert-butyl
4-{4-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1H-1,2,3-triazol-1-yl}pip-
eridine-1-carboxylate (48 mg) was dissolved in methylene chloride
(4.0 ml). To the solution was added trifluoroacetic acid (1.0 ml),
and the mixture was stirred at room temperature for 1 hour.
[0615] The reaction solution was concentrated under reduced
pressure to give a quantitative amount of the title compound.
[0616] LC-MS, m/z; 329 [M+H]+
Reference Examples 142 to 143
Preparation of
7-fluoro-1-[5-(piperidin-4-yl)-1,3-thiazol-2-yl]-3-(propan-2-yl)-1H-indaz-
ole trifluoroacetate and
7-fluoro-1-[2-(piperidin-4-yl)-1,3-thiazol-5-yl]-3-(propan-2-yl)-1H-indaz-
ole trifluoroacetate
##STR00107##
[0618] (1) 7-Fluoro-3-isopropyl-1H-indazole was dissolved in DMF
(8.9 ml). To the solution was added 55% sodium hydride (262 mg) at
ice temperature, and the mixture was stirred at ice temperature for
15 minutes. Then, 2,5-dibromothiazole (1.46 g) was added thereto,
and the mixture was heated to 60.degree. C. and stirred for 5
hours. To the reaction solution was added water, and the mixture
was extracted with ethyl acetate. The organic layer was washed with
water and brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by
octadecyl-silica-gel chromatography (column; Hi-Flash.TM.,
developing solvent: acetonitrile/water) to give a mixture of
1-(5-bromo-1,3-thiazol-2-yl)-7-fluoro-3-(propan-2-yl)-1H-indazole
and
1-(2-bromo-1,3-thiazol-5-yl)-7-fluoro-3-(propan-2-yl)-1H-indazole
(743 mg).
[0619] (2) The mixture of
1-(5-bromo-1,3-thiazol-2-yl)-7-fluoro-3-(propan-2-yl)-1H-indazole
and
1-(2-bromo-1,3-thiazol-5-yl)-7-fluoro-3-(propan-2-yl)-1H-indazole
(170 mg), 1-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol
ester (186 mg), tetrakis(triphenylphosphine)palladium (0) (29 mg),
and sodium carbonate (106 mg) were mixed in a solvent of water (1
ml) and DMF (4.2 ml). The mixture was stirred at 70.degree. C. for
1 hour under nitrogen atmosphere. To the reaction mixture was added
water, and the mixture was extracted with a mixed solvent of ethyl
acetate/toluene. The organic layer was washed with water and
saline, dried over anhydrous sodium sulfate, concentrated under
reduced pressure, and the residue was purified by silica-gel
chromatography (column; Hi-Flash.TM., developing solvent:
hexane/ethyl acetate) to give a mixture of tert-butyl
4-{2-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,3-thiazol-5-yl}-3,6-dih-
ydropyridine-1 (2H)-carboxylate and tert-butyl
4-{5-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,3-thiazol-2-yl}-3,6-dih-
ydropyridine-1 (2H)-carboxylate (212 mg).
[0620] (3) The mixture of tert-butyl
4-{2-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,3-thiazol-5-yl}-3,6-dih-
ydropyridine-1 (2H)-carboxylate and tert-butyl
4-{5-[7-fluoro-3-(propan-2-yl)-1,3-indazol-1-yl]-1,3-thiazol-2-yl}-3,6-di-
hydropyridine-1 (2H)-carboxylate (100 mg) and 5% palladium carbon
(20 mg) was mixed in ethyl acetate (3.0 ml), and the mixture was
stirred at room temperature for 6 hours under hydrogen atmosphere
(normal pressure). To the mixture was added 10% palladium carbon
(50 mg), and the resultant mixture was further stirred at room
temperature for 16 hours under hydrogen atmosphere (normal
pressure). Then, the reaction mixture was filtered through Celite,
the filtrate was concentrated under reduced pressure, and the
residue was purified by silica-gel chromatography (column;
Hi-Flash.TM., developing solvent: hexane/ethyl acetate) to give
tert-butyl
4-{2-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,3-thiazol-5-yl}piperidi-
ne-1-carboxylate (56 mg) and tert-butyl
4-{5-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,3-thiazol-2-yl}piperidi-
ne-1-carboxylate (21 mg).
[0621] (4) Each of the tert-butyl
4-{2-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,3-thiazol-5-yl}piperidi-
ne-1-carboxylate (56 mg) and the tert-butyl
4-{5-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,3-thiazol-2-yl}piperidi-
ne-1-carboxylate (21 mg) was dissolved in methylene chloride, and
trifluoroacetic acid was added thereto. Each of the mixed solutions
was stirred at room temperature. After confirming the completion of
the reactions, each of the reaction mixtures was concentrated to
give a quantitative amount of the two title compounds.
[0622] LC-MS, m/z; 345 [M+H]+
Reference Example 144
Preparation of
7-fluoro-1-[5-(piperidin-4-yl)-1H-imidazol-2-yl]-3-(propan-2-yl)-1H-indaz-
ole
##STR00108##
[0624] (1)
7-Fluoro-N'-hydroxy-3-(propan-2-yl)-1H-indazole-1-carboximidami- de
(236 mg), acetic anhydride (112 mg) and 5% palladium carbon (100
mg) were mixed in acetic acid (23 ml), and the mixture was stirred
at room temperature for 5 hours under hydrogen atmosphere (normal
pressure). The reaction mixture was filtered through Celite, the
filtrate was concentrated under reduced pressure, and the residue
was purified by size exclusion column chromatography (Moving bed:
chloroform) to give
7-fluoro-3-(propan-2-yl)-1H-indazole-1-carboximidamide (100
mg).
[0625] (2) The
7-fluoro-3-(propan-2-yl)-1H-indazole-1-carboximidamide (55 mg),
benzyl 4-(2-bromoacetyl)piperidine-1-carboxylate (85 mg) and
potassium carbonate (159 mg) were mixed in DMF (1.2 ml), and the
mixture was stirred at room temperature for 19 hours. To the
reaction mixture was added water, and the resultant was extracted
with a mixed solvent of ethyl acetate/toluene. The organic layer
was washed with water and brine, dried over anhydrous sodium
sulfate, and concentrated. The residue was purified by silica-gel
chromatography (column; Hi-Flash.TM., developing solvent:
hexane/ethyl acetate) to give benzyl
4-{2-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1H-imidazol-5-yl}piperidi-
ne-1-carboxylate (61 mg).
[0626] (3) The benzyl
4-{2-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1H-imidazol-5-yl}piperidi-
ne-1-carboxylate (61 mg) and 5% palladium carbon (13 mg) were mixed
in ethyl acetate (6.1 ml), and the mixture was stirred at room
temperature for 2 hours under hydrogen atmosphere (normal
pressure). To the mixture was further added 10% palladium carbon
(30 mg), and the resultant mixture was stirred at room temperature
for 19 hours under hydrogen atmosphere (normal pressure). The
reaction mixture was filtered through Celite, and the filtrate was
concentrated under reduced pressure to give the title compound (30
mg).
[0627] LC-MS, m/z; 328 [M+H]+
Reference Example 145
Preparation of
cis-1-(tert-butoxycarbonyl)-3-methoxypiperidine-4-carboxylic
acid
##STR00109##
[0629] (1) To 1-tert-butyl 4-ethyl
3-oxopiperidine-1,4-dicarboxylate (4.9 g) of tetrahydrofuran (50
ml) was gradually added 60% sodium hydride (1.1 g). The mixture was
stirred at room temperature for 1 hour. To the reaction solution
was added dimethyl sulfate (2.5 ml), and the mixture was stirred at
60.degree. C. for 3 hours. The reaction solution was cooled to room
temperature. To the solution was added saturated sodium hydrogen
carbonate aqueous solution (50 ml), and the mixture was extracted
with ethyl acetate (20 ml, .times.3). The organic layer was dried
over anhydrous sodium sulfate, filtered, and concentrated under
reduced pressure. The residue was purified by silica-gel
chromatography to give 1-tert-butyl 4-ethyl
3-methoxy-5,6-dihydropyridine-1,4(2H-dicarboxylate (2.4 g).
[0630] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20-1.28 (3H, m), 1.45
(9H, d, J=0.6 Hz), 2.34-2.44 (2H, m), 3.36-3.45 (2H, m), 3.75 (3H,
s), 4.02-4.22 (4H, m).
[0631] LC-MS, m/z; 286 [M+H]+
[0632] (2) To the 1-tert-butyl 4-ethyl
3-methoxy-5,6-dihydropyridine-1,4(2H)-dicarboxylate (2.4 g) in
ethanol (20 ml) was added 10% palladium carbon (300 mg). The
mixture was stirred at room temperature for 1 hour under hydrogen
atmosphere. The reaction solution was filtered through Celite. To
the filtrate was added 2 mol/L aqueous sodium hydroxide (15 ml),
and the mixture was stirred for 3 hours. The reaction solution was
adjusted to pH 2 with 1 mol/L HCl, ethanol was removed under
reduced pressure, the aqueous layer was extracted with ethyl
acetate (10 m1, x3). The organic layer was dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure,
and the residue was recrystallized from diethylether to give the
title compound (830 mg).
[0633] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (9H, s), 1.67 (1H, d,
J=14.7 Hz), 2.00 (1H, ddd, J=25.2, 11.7, 4.3 Hz), 2.55-2.64 (1H,
m), 2.66-2.94 (2H, m), 3.40 (3H, s), 3.67-3.76 (1H, m), 3.84-4.21
(1H, m), 4.24-4.32 (1H, m).
[0634] LC-MS, m/z; 260 [M+H]+
[0635] The compounds in the following table (i.e. Reference
Examples 146 to 149) were prepared in the same manner as in
Reference Example 033 or Reference Example 060 except that the
3-ethyl-6-fluoro-N'-hydroxy-1H-indazole-1-carboximidamide of
Reference Example 033 and Reference Example 060 was replaced with
the corresponding starting compound and carboxylic acid.
##STR00110##
Wherein (B-2) means each cyclic amino structure shown in the
following table; and the Boc group is attached to the nitrogen atom
in the cyclic amine of (B-2).
TABLE-US-00012 TABLE 12 Ref. Compound .sup.1H-NMR/LC-MS, Ex. (B-2)
Name m/z 146.sup.1) ##STR00111## tert-butyl 4-fluoro- 4-{3-[7-
fluoro-3-(propan-2- yl)-1H- indazol-1-yl]-1,2,4- oxadiazol-
5-yl}piperidine-1- carboxylate LC-MS, m/z; 448 [M + H]+ 147.sup.1)
##STR00112## tert-butyl 4-{3-[7- fluoro-3- (propan-2-yl)-1H-
indazol-1- yl]-1,2,4-oxadiazol- 5-yl}-3- methylpiperidine-1-
carboxylate LC-MS, m/z; 444 [M + H]+ 148.sup.2) ##STR00113##
tert-butyl (3S,4S)-4- {3-[7- fluoro-3-(propan-2- yl)-1H-
indazol-1-yl]-1,2,4- oxadiazol- 5-yl}-3- methoxypiperidine- 1-
carboxylate and tert-butyl (3R,4R)- 4-{3-[7- fluoro-3-(propan-2-
yl)-1H- indazol-1-yl]-1,2,4- oxadiazol- 5-yl}-3- methoxypiperidine-
1- carboxylate LC-MS, m/z; 460 [M + H]+ 149.sup.1) ##STR00114##
tert-butyl 4-{3-[7- fluoro-3- (propan-2-yl)-1H- indazol-1-
yl]-1,2,4-oxadiazol- 5-yl}-4- methylpiperidine-1- carboxylate
LC-MS, m/z; 444 [M + H]+ .sup.1)In the same manner as in Reference
Example 033. .sup.2)In the same manner as in Reference Example
060.
Reference Example 150
Preparation of
7-fluoro-N'-hydroxy-3-methoxy-1H-indazole-1-carboximidamide
##STR00115##
[0637] (1) Methyl 2,3-difluorobenzoate (2.00 g) and hydrazine
monohydrate (2.91 g) was mixed in 1,4-dioxane (40 ml), and the
mixture was heated at 100.degree. C. for 19 hours. To the reaction
mixture was added silica-gel, and the mixture was concentrated. The
residue was purified by silica-gel chromatography (column;
Hi-Flash.TM., developing solvent: chloroform/methanol) to give
7-fluoro-1H-indazol-3-ol (1.73 g).
[0638] (2) The 7-fluoro-1H-indazol-3-ol (1.68 g) and DMAP (67 mg)
was mixed in acetonitrile (17 ml), and to the mixture was added
dropwise di-tert-butyl dicarbonate (2.53 g) in acetonitrile (17 ml)
at room temperature. The reaction mixture was stirred at room
temperature for 5 hours, and concentrated under reduced pressure.
The residue was purified by silica-gel chromatography (column;
Hi-Flash.TM., developing solvent: chloroform/methanol) and further
washed with ethyl acetate to give tert-butyl
7-fluoro-3-hydroxy-1H-indazole-1-carboxylate (1.82 g).
[0639] (3) The tert-butyl
7-fluoro-3-hydroxy-1H-indazole-1-carboxylate (126 mg), methyl
iodide (255 mg) and silver carbonate (489 mg) were mixed in
acetonitrile (2.5 ml), and the mixture was stirred at 80.degree. C.
for 4 hours. The residue was purified by silica-gel chromatography
(column; Hi-Flash.TM., developing solvent: hexane/ethyl acetate) to
give tert-butyl 7-fluoro-3-methoxy-1H-indazole-1-carboxylate (105
mg).
[0640] (4) Tert-butyl 7-fluoro-3-methoxy-1H-indazole-1-carboxylate
(105 mg) was added to 4 N HCl (in 1,4-dioxane), and the mixture was
stirred at room temperature for 16 hours. The reaction mixture was
concentrated under reduced pressure to give a quantitative amount
of 7-fluoro-3-methoxy-1H-indazole.
[0641] (5) The title compound was prepared in the same manner as in
Reference Example 016 except that the 3-ethyl-6-fluoro-1H-indazole
was replaced with the above 7-fluoro-3-methoxy-1H-indazole.
[0642] TLC Rf=0.52 (CHCl.sub.3/MeOH=20/1)
Example 001
Preparation of
3-ethyl-6-fluoro-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate
##STR00116##
[0644] Tert-butyl
4-[3-(3-ethyl-6-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidine-1-
-carboxylate (1.66 g) was dissolved in dichloromethane (5.0 ml). To
the solution was added trifluoroacetic acid (2.0 ml), and the
mixture was stirred at room temperature for 30 minutes. The
reaction solution was evaporated under reduced pressure, and the
residue was crystallized by adding diethyl ether (20 ml) thereto.
The resultant crystal was collected on a filter to give the title
compound (1.56 g) as a white solid.
[0645] LC-MS, m/z; 316 [M+H]+
[0646] The compounds in the following table (i.e. Examples 002 to
011) were prepared in the same manner as in Example 001 except that
the tert-butyl
4-[3-(3-ethyl-6-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidine-1-
-carboxylate was replaced with the corresponding starting compound
(which is described in Reference Examples 033 to 049).
##STR00117##
TABLE-US-00013 TABLE 13 Com- pound LC-MS, Ex. R.sup.3 R.sup.4
R.sup.5 R.sup.6 R.sup.7 Name m/z 002 Et F H H H 3-ethyl-4- LC-MS,
fluoro- m/z; 1-[5- 316 (piperidin- [M + H]+ 4- yl)-1,2,4-
oxadiazol- 3-yl]- 1H- indazole trifluoroacetate 003 Et H F H H
3-ethyl-5-fluoro- LC-MS, 1-[5-(piperidin- m/z; 4- 316 yl)-1,2,4- [M
+ H]+ oxadiazol-3-yl]- 1H-indazole trifluoroacetate 004 Et H H H F
3-ethyl-7- LC-MS, fluoro- m/z; 1-[5-(piperidin- 316 4- [M + H]+
yl)-1,2,4- oxadiazol-3-yl]- 1H-indazole trifluoroacetate 005
##STR00118## H H H H 3-(2- methylpropyl)- 1- [5-(piperidin-4-
yl)-1,2,4- oxadiazol-3-yl]- 1H-indazole trifluoroacetate LC-MS,
m/z; 326 [M + H]+ 006 .sup.iPr H H H F 7-fluoro-1-[5- LC-MS,
(piperidin-4-yl)- m/z; 1,2,4-oxadiazol- 330 3- [M + H]+
yl]-3-(propan-2- yl)-1H-indazole trifluoroacetate 007 Et H H MeO H
3-ethyl-6- LC-MS, methoxy- m/z; 1-[5-(piperidin- 328 4- [M + H]+
yl)-1,2,4- oxadiazol-3-yl]- 1H-indazole trifluoroacetate 008
##STR00119## H H H H 3- (methoxymethyl)- 1-[5-(piperidin-4-
yl)-1,2,4- oxadiazol-3-yl]- 1H-indazole trifluoroacetate LC-MS,
m/z; 314 [M + H]+ 009 ##STR00120## H H H H 3- (difluoromethyl)-
1-[5-(piperidin-4- yl)-1,2,4- oxadiazol-3-yl]- 1H-indazole
trifluoroacetate LC-MS, m/z; 320 [M + H]+ 010 Br H H H H
3-bromo-1-[5- LC-MS, (piperidin-4-yl)- m/z; 1,2,4-oxadiazol- 348 3-
[M + H]+ yl]-1H-indazole trifluoroacetate 011 Et H H H H
3-ethyl-1-[5- LC-MS, (piperidin-4-yl)- m/z; 1,2,4-oxadiazol- 298 3-
[M + H]+ yl]-1H-indazole trifluoroacetate
Example 012
Preparation of
1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-3-(propan-2-yl)-1H-indazole
hydrochloride
##STR00121##
[0648] To tert-butyl
4-{3-[3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}piperidine-1--
carboxylate (0.64 g) was added 4 N HCl/1,4-dioxane (15 ml), and the
mixture was stirred at room temperature for 30 minutes. The
crystallized solid was collected on a filter, washed with hexane,
dried at 60.degree. C. under reduced pressure to give the title
compound (0.40 g) as a white solid.
[0649] LC-MS, m/z; 312 [M+H]+
[0650] The compounds in the following table (i.e. Examples 013 to
019) were prepared in the same manner as in Example 012 except that
the tert-butyl
4-{3-[3-(propan-2-yl)-11'-indazol-1-yl]-1,2,4-oxadiazol-5-yl}piperidine-1-
-carboxylate was replaced with the corresponding starting compound
(which is described in Reference Examples 033 to 049).
##STR00122##
TABLE-US-00014 TABLE 14 Compound .sup.1H-NMR/ Ex. R.sup.3 R.sup.4
R.sup.5 R.sup.6 R.sup.7 Name LC-MS, m/z 013 Et H H H H
3-ethyl-1-[5- LC-MS, m/z; (piperidin-4- 298 [M + H]+ yl)-1,2,4-
oxadiazol-3- yl]-1H-indazole hydrochloride 014 ##STR00123## H H H H
3-cyclopropyl- 1-[5- (piperidin-4- yl)-1,2,4- oxadiazol-3-
yl]-1H-indazole hydrochloride .sup.1H-NMR (400 MHz, CDCl.sub.3):
.delta. 0.85-0.97 (m, 2H), 0.98-1.09 (m, 2H), 2.06-2.35 (m, 5H),
2.89- 3.01 (m, 2H), 3.15-3.28 (m, 2H), 7.11 (t, J = 7.4 Hz, 1H),
7.34 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 8.20 (d, J =
8.8 Hz, 1H). 015 Me H H H H 3-methyl-1-[5- LC-MS, m/z;
(piperidin-4- 284 [M + H]+ yl)-1,2,4- oxadiazol-3- yl]-1H-indazole
hydrochloride 016 ##STR00124## H H H H 3-cyclobutyl-1-
[5-(piperidin- 4-yl)-1,2,4- oxadiazol-3- yl]-1H-indazole
hydrochloride No data 017 Cl H H H H 3-chloro-1-[5- LC-MS, m/z;
(piperidin-4- 304 [M + H]+ yl)-1,2,4- oxadiazol-3- yl]-1H-indazole
hydrochloride 018 .sup.iPr H H H F 7-fluoro-1-[5- LC-MS, m/z;
(piperidin-4- 330 [M + H]+ yl)-1,2,4- oxadiazol-3- yl]-3-(propan-
2-yl)-1H- indazole hydrochloride 019 Et H H H Cl 7-chloro-3- LC-MS,
m/z; ethyl-1-[5- 332 [M + H]+ (piperidin-4- yl)-1,2,4- oxadiazol-3-
yl]-1H-indazole hydrochloride
[0651] The compounds in the following table (i.e. Examples 020 to
022) were prepared in the same manner as in Example 001 or Example
012 except that the corresponding starting compound (which is
described in Reference Examples 050 to 052) was used.
##STR00125##
[0652] Wherein HX is hydrochloric acid or trifluoroacetic acid.
TABLE-US-00015 TABLE 15 Ex. R.sup.3 R.sup.4 R.sup.5 R.sup.6 R.sup.7
Compound Name LC-MS, m/z 020 Et H H H H 1-[5-(azetidin-3-yl)-
LC-MS, m/z; 1,2,4-oxadiazol-3-yl]- 271 [M + H]+ 3-ethyl-1H-indazole
hydrochloride 021 .sup.iPr H H H H 1-[5-(azetidin-3-yl)- .sup.1H
NMR (400 1,2,4-oxadiazol-3-yl]- MHz, CDCl.sub.3) .delta.
3-(propan-2-yl)-1H- 1.47 (s, 9 indazole hydrochloride H), 1.52 (d,
6 H), 3.53 (m, 1 H), 4.12 (dd, J = 7.6 Hz, 15.2 Hz, 1 H), 4.38 (d,
2 H), 4.40 (d, 2 H), 7.32 (t, J = 7.6 Hz, 1 H), 7.58 (t, J = 7.6
Hz, 1 H), 7.83 (d, J = 8.0 Hz, 1 H), 8.28 (d, J = 8.4 Hz, 1H). 022
Et H H F H 1-[5-(azetidin-3-yl)- LC MS, m/z; 1,2,4-oxadiazol-3-yl]-
288 [M + H]+ 3-ethyl-6-fluoro-1H- indazole trifluoroacetate
Example 023
Preparation of tert-butyl
4-(2-{4-[3-(3-ethyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}-
ethyl)piperidine-1-carboxylate
##STR00126##
[0654]
3-Ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate (100 mg) was suspended in N,N-dimethylformamide (3
ml). To the suspension were added tert-butyl
4-(2-iodoethyl)piperidine-1-carboxylate (115 mg) and potassium
carbonate (135 mg), and the mixture was refluxed overnight. The
reaction solution was cooled to room temperature and water was
added thereto. The mixture was extracted with ethyl acetate, the
organic layer was washed with water and brine, dried over sodium
sulfate and filtered, and the filtrate was concentrated under
reduced pressure. The residue was purified by silica-gel
chromatography (column; Hi-Flash.TM. Amino Column, developing
solvent: hexane/ethyl acetate=2:1) to give the title compound (58
mg) as a white solid.
[0655] LC-MS, m/z; 509 [M+H]+
Example 024
Preparation of tert-butyl
4-({4-[3-(3-ethyl-6-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidi-
n-1-yl}methyl)piperidine-1-carboxylate
##STR00127##
[0657]
3-Ethyl-6-fluoro-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-ind-
azole trifluoroacetate (150 mg) was suspended in acetonitrile (4.00
ml). To the suspension were added potassium carbonate (290 mg),
tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (194 mg) and
sodium iodide (58 mg), and the mixture was stirred under reflux
overnight. The reaction solution was cooled to room temperature,
water (20 ml) was added thereto, and the mixture was extracted with
ethyl acetate (20 ml). The organic layer was washed with water (20
ml.times.2) again, and dried over sodium sulfate. The organic layer
was evaporated under reduced pressure, and the residue was purified
by silica-gel chromatography (column; Hi-Flash.TM. Amino Column,
developing solvent: hexane/ethyl acetate=2/1) to give the title
compound (160 mg) as a colorless oil.
[0658] LC-MS, m/z; 513 [M+H]+
[0659] The compounds in the following table (i.e. Examples 025 to
026) were prepared in the same manner as in Example 024 except that
the
3-ethyl-6-fluoro-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate was replaced with the corresponding starting
compound.
##STR00128##
[0660] Wherein HX is hydrochloric acid or trifluoroacetic acid.
TABLE-US-00016 TABLE 16 Ex. R.sup.7 Compound Name LC-MS, m/z 025 H
tert-butyl 4-({4-[3-(3-ethyl-1H-indazol- LC-MS, m/z;
1-yl)-1,2,4-oxadiazol-5-yl]piperidin-1- 495 [M + H]+
yl}methyl)piperidine-1-carboxylate 026 F tert-butyl
4-({4-[3-(3-ethyl-7-fluoro-1H- LC-MS, m/z;
indazol-1-yl)-1,2,4-oxadiazol-5- 513 [M + H]+
yl]piperidin-1-yl}methyl)piperidine-1- carboxylate
Example 027
Preparation of tert-butyl
4-[(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-
piperidin-1-yl)methyl]piperidine-1-carboxylate
##STR00129##
[0662]
7-Fluoro-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-3-(propan-2-yl-
)-1H-indazole trifluoroacetate (1.43 g) was dissolved in
dichloromethane (20 ml). To the solution were added
1-Boc-4-piperidine-carboxaldehyde (1.37 g) and triacetoxysodium
borohydride (1.36 g), and the mixture was stirred at room
temperature overnight. To the reaction mixture was added saturated
sodium bicarbonate aqueous solution, and the mixture was extracted
with chloroform. The organic layer was dried over sodium sulfate
and filtered, and the filtrate was concentrated under reduced
pressure. The residue was purified by silica-gel chromatography
(column; Hi-Flash.TM. Amino Column, developing solvent:
hexane/ethyl acetate=1/1) to give tert-butyl
4-[(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazole-1-yl]-1,2,4-oxadiazol-5-yl-
}piperidin-1-yl)methyl]piperidine-1-carboxylate (1.69 g) as a
colorless oil.
[0663] LCMS, m/z; 527 [M+H]+
Example 028
Preparation of tert-butyl
(2S)-2-({4-[3-(3-ethyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidin-1--
yl}methyl)pyrrolidine-1-carboxylate
##STR00130##
[0665]
3-Ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate (100 mg) was dissolved in dichloromethane (5 ml).
To the solution were added
(S)-(-)-1-tert-butoxycarbonyl-2-pyrrolidinecarbaldehyde (73 mg) and
triacetoxysodium borohydride (155 mg) at 0.degree. C. with
stirring, and the mixture was stirred at room temperature for 3
hours. To the reaction solution was added saturated sodium
bicarbonate aqueous solution, and the mixture was extracted with
ethyl acetate. The organic layer was washed with water and brine,
dried over sodium sulfate, and concentrated under reduced pressure.
The residue was purified by silica-gel chromatography (column;
Hi-Flash.TM. Amino Column, developing solvent: hexane/ethyl
acetate=1:1) to give the title compound (108 mg) as a white
solid.
[0666] LC-MS, m/z; 481 [M+H]+
[0667] The compounds in the following table (i.e. Examples 029 to
032) were prepared in the same manner as in Example 028 except that
the 3-ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate was replaced with the corresponding starting
compound.
##STR00131##
Wherein HX is hydrochloric acid or trifluoroacetic acid.
TABLE-US-00017 TABLE 17 Ex. R.sup.3 R.sup.6 R.sup.7 Compound Name
LC-MS, m/z 029 Me F H tert-butyl (2S)-2-({4-[3-(6- LC-MS,
fluoro-3-methyl-1H-indazol-1- m/z; yl)-1,2,4-oxadiazol-5- 485 [M +
H]+ yl]piperidin-1- yl}methyl)pyrrolidine-1- carboxylate 030 Et F H
tert-butyl (2S)-2-({4-[3-(3- LC-MS,
ethyl-6-fluoro-1H-indazol-1-yl)- m/z;
1,2,4-oxadiazol-5-yl]piperidin- 499 [M + H]+
1-yl}methyl)pyrrolidine-1- carboxylate 031 Et H F tert-butyl
(2S)-2-({4-[3-(3- LC-MS, ethyl-7-fluoro-1H-indazol-1-yl)- m/z;
1,2,4-oxadiazol-5-yl]piperidin- 499 [M + H]+
1-yl}methyl)pyrrolidine-1- carboxylate 032 .sup.iPr H F tert-butyl
(2S)-2-[(4-{3-[7- LC-MS, fluoro-3-(propan-2-yl)-1H- m/z;
indazol-1-yl]-1,2,4-oxadiazol-5- 513 [M + H]+ yl}piperidin-1-
yl)methyl]pyrrolidine-1- carboxylate
[0668] The compounds in the following table (i.e. Examples 033 to
034) were prepared in the same manner as in Example 028 except that
the 3-ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and
(S)-(-)-1-tert-butoxycarbonyl-2-pyrrolidinecarbaldehyde were
replaced with the corresponding starting compound and
(R)-(+)-1-tert-butoxycarbonyl-2-pyrrolidinecarbaldehyde,
respectively.
##STR00132##
Wherein HX is hydrochloric acid or trifluoroacetic acid.
TABLE-US-00018 TABLE 18 Ex. R.sup.7 Compound Name LC-MS, m/z 033 H
tert-butyl (2R)-2-({4-[3-(3-ethyl-1H- LC-MS, m/z;
indazol-1-yl)-1,2,4-oxadiazol-5- 481 [M + H]+
yl]piperidin-1-yl}methyl)pyrrolidine-1- carboxylate 034 F
tert-butyl (2R)-2-({4-[3-(3-ethyl-7- LC-MS, m/z;
fluoro-1H-indazol-1-yl)-1,2,4- 499 [M + H]+
oxadiazol-5-yl]piperidin-1- yl}methyl)pyrrolidine-1-carboxylate
Example 035
Preparation of tert-butyl
(3S)-3-({4-[3-(3-ethyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidin-1--
yl}methyl)pyrrolidine-1-carboxylate
##STR00133##
[0670]
3-Ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate (100 mg) was suspended in N,N-dimethylformamide (3
ml). To the suspension were added tert-butyl
(3R)-3-(iodomethyl)pyrrolidine-1-carboxylate (106 mg) and potassium
carbonate (135 mg), and the mixture was refluxed overnight. The
reaction solution was cooled to room temperature and water was
added thereto. The mixture was extracted with ethyl acetate, the
organic layer was washed with water and brine, dried over sodium
sulfate and filtered, and the filtrate was concentrated under
reduced pressure. The residue was purified by silica-gel
chromatography (column; Hi-Flash.TM. Amino Column, developing
solvent: hexane/ethyl acetate=1:1) to give the title compound (84
mg) as a white solid.
[0671] LC-MS, m/z; 481 [M+H]+
[0672] The compounds in the following table (i.e. Examples 036 to
038) were prepared in the same manner as in Example 035 except that
the 3-ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate was replaced with the corresponding starting
compound.
##STR00134##
Wherein HX is hydrochloric acid or trifluoroacetic acid.
TABLE-US-00019 TABLE 19 Ex. R.sup.3 R.sup.6 R.sup.7 Compound Name
LC-MS, m/z 036 Et H F tert-butyl (3S)-3-({4-[3-(3- LC-MS, m/z;
ethyl-7-fluoro-1H-indazol-1- 499 [M + H]+ yl)-1,2,4-oxadiazol-5-
yl]piperidin-1- yl}methyl)pyrrolidine-1- carboxylate 037 Et F H
tert-butyl (3S)-3-({4-[3-(3- LC-MS, m/z;
ethyl-6-fluoro-1H-indazol-1- 499 [M + H]+ yl)-1,2,4-oxadiazol-5-
yl]piperidin-1- yl}methyl)pyrrolidine-1- carboxylate 038 .sup.iPr H
F tert-butyl (3S)-3-[(4-{3-[7- LCMS, m/z;
fluoro-3-(propan-2-yl)-1H- 513 [M + H]+
indazol-1-yl]-1,2,4-oxadiazol- 5-yl}piperidin-1-
yl)methyl]pyrrolidine-1- carboxylate
[0673] The compounds in the following table (i.e. Examples 039 to
042) were prepared in the same manner as in Example 035 except that
the 3-ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and tert-butyl
(3R)-3-(iodomethyl)pyrrolidine-1-carboxylate were replaced with the
corresponding starting compound and tert-butyl
(3S)-3-(iodomethyl)pyrrolidine-1-carboxylate, respectively.
##STR00135##
Wherein HX is hydrochloric acid or trifluoroacetic acid.
TABLE-US-00020 TABLE 20 Ex. R.sup.3 R.sup.6 R.sup.7 Compound Name
LC-MS, m/z 039 Et H H tert-butyl (3R)-3-({4-[3-(3- LC-MS, m/z;
ethyl-1H-indazol-1-yl)-1,2,4- 481 [M + H]+
oxadiazol-5-yl]piperidin-1- yl}methyl)pyrrolidine-1- carboxylate
040 Et H F tert-butyl (3R)-3-({4-[3-(3- LC-MS, m/z;
ethyl-7-fluoro-1H-indazol-1- 499 [M + H]+ yl)-1,2,4-oxadiazol-5-
yl]piperidin-1- yl}methyl)pyrrolidine-1- carboxylate 041 Et F H
tert-butyl (3R)-3-({4-[3-(3- LC-MS, m/z;
ethyl-6-fluoro-1H-indazol-1- 499 [M + H]+ yl)-1,2,4-oxadiazol-5-
yl]piperidin-1- yl}methyl)pyrrolidine-1- carboxylate 042 .sup.iPr H
F tert-butyl (3R)-3-[(4-{3-[7- LCMS, m/z;
fluoro-3-(propan-2-yl)-1H- 513 [M + H]+
indazol-1-yl]-1,2,4-oxadiazol- 5-yl}piperidin-1-
yl)methyl]pyrrolidine-1- carboxylate
[0674] The compounds in the following table (i.e. Examples 043 to
046) were prepared in the same manner as in Example 028 except that
the 3-ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and
(S)-(-)-1-tert-butoxycarbonyl-2-pyrrolidinecarbaldehyde were
replaced with the corresponding starting compound and tert-butyl
3-formylazetidine-1-carboxylate, respectively.
##STR00136##
Wherein HX is hydrochloric acid or trifluoroacetic acid.
TABLE-US-00021 TABLE 21 Ex. R.sup.3 R.sup.6 R.sup.7 Compound Name
LC-MS, m/z 043 Et F H tert-butyl 3-({4-[3-(3-ethyl- LC-MS, m/z;
6-fluoro-1H-indazol-1-yl)- 485 [M + H]+ 1,2,4-oxadiazol-5-
yl]piperidin-1- yl}methyl)azetidine-1- carboxylate 045 Et H F
tert-butyl 3-({4-[3-(3-ethyl- LC-MS, m/z;
7-fluoro-1H-indazol-1-yl)- 485 [M + H]+ 1,2,4-oxadiazol-5-
yl]piperidin-1- yl}methyl)azetidine-1- carboxylate 046 .sup.iPr H F
tert-butyl 3-[(4-{3-[7-fluoro- LC-MS, m/z;
3-(propan-2-yl)-1H-indazol-1- 499 [M + H]+ yl]-1,2,4-oxadiazol-5-
yl}piperidin-1- yl)methyl]azetidine-1- carboxylate
[0675] The compounds in the following table (i.e. Reference
Examples 047 to 051) were prepared in the same manner as in Example
028 except that the
3-ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and
(S)-(-)-1-tert-butoxycarbonyl-2-pyrrolidinecarbaldehyde were
replaced with the corresponding starting compound and tert-butyl
4-oxopiperidine-1-carboxylate, respectively.
##STR00137##
Wherein HX is hydrochloric acid or trifluoroacetic acid.
TABLE-US-00022 TABLE 22 Ex. R.sup.3 R.sup.6 R.sup.7 Compound Name
LC-MS, m/z 047 Et H H tert-butyl 4-[3-(3- LC-MS, m/z;
ethyl-1H-indazol-1- 481 [M + H]+ yl)-1,2,4- oxadiazol-5-yl]-
1,4'-bipiperidine- 1'-carboxylate 048 Et F H tert-butyl 4-[3-(3-
LC-MS, m/z; ethyl-6-fluoro-1H- 499 [M + H]+ indazol-1-yl)-
1,2,4-oxadiazol-5- yl]-1,4'- bipiperidine-1'- carboxylate 049 Et H
F tert-butyl 4-[3-(3- LC-MS, m/z; ethyl-7-fluoro-1H- 499 [M + H]+
indazol-1-yl)- 1,2,4-oxadiazol-5- yl]-1,4'- bipiperidine-1'-
carboxylate 050 .sup.iPr H F tert-butyl 4-{3-[7- LC-MS, m/z;
fluoro-3-(propan-2- 513 [M + H]+ yl)-1H-indazol-1- yl]-1,2,4-
oxadiazol-5-yl}- 1,4'-bipiperidine- 1'-carboxylate 051 Et H Cl
tert-butyl 4-[3-(7- LC-MS, m/z; chloro-3-ethyl-1H- 515 [M + H]+
indazol-1-yl)- 1,2,4-oxadiazol-5- yl]-1,4'- bipiperidine-1'-
carboxylate
Example 052
Preparation of tert-butyl
4-{3-[3-(3-ethyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]azetidin-1-yl}pipe-
ridine-1-carboxylate
##STR00138##
[0677] The title compound was prepared in the same manner as in
Example 028 except that the
3-ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and
(S)-(-)-1-tert-butoxycarbonyl-2-pyrrolidinecarbaldehyde were
replaced with
1-[5-(azetidin-3-yl)-1,2,4-oxadiazol-3-yl]-3-ethyl-1H-indazole
hydrochloride and tert-butyl 4-oxopiperidine-1-carboxylate,
respectively.
[0678] LC-MS, m/z; 396 [M+H-tBu]+
Example 053
Preparation of
7-fluoro-1-{5-[1-(piperidin-4-ylmethyl)piperidin-4-yl]-1,2,4-oxadiazol-3--
yl}-3-(propan-2-yl)-1H-indazole dihydrochloride
##STR00139##
[0680] To tert-butyl
4-[(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-
piperidin-1-yl)methyl]piperidine-1-carboxylate (1.69 g) was added
4N HCl/dioxane (13.5 ml) at 0.degree. C., and the mixture was
reacted at room temperature for 3 hours. The reaction solution was
concentrated under reduced pressure, toluene (5 ml) was added
thereto and the mixture was concentrated under reduced pressure
(.times.3). The residue was crystallized by adding ethyl acetate.
Then, the resultant was concentrated under reduced pressure to give
7-fluoro-1-{5-[1-(piperidin-4-ylmethyl)piperidin-4-yl]-1,2,4-oxadiazol-3--
yl}-3-(propan-2-yl)-1H-indazole dihydrochloride (1.59 g) as a
colorless crystal.
[0681] LCMS, m/z; 427[M+H]+
Example 054
Preparation of
1-{5-[1-(azetidin-3-ylmethyl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}-7-fluo-
ro-3-(propan-2-yl)-1H-indazole bis(trifluoroacetate)
##STR00140##
[0683] Tert-butyl
3-[(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-
piperidin-1-yl)methyl]azetidine-1-carboxylate (1.65 g) was
dissolved in dichloromethane (4.00 ml). To the solution was added
trifluoroacetic acid (4.00 ml), and the mixed solution was stirred
at room temperature for 1 hour. The reaction solution was
evaporated under reduced pressure, and the residue was crystallized
from diethyl ether (20 ml). The resultant crystal was collected on
a filter to give the title compound (1.96 g) as a white solid.
[0684] LC-MS, m/z; 399 [M+H]+
[0685] The compounds in the following table (i.e. Examples 055 to
080) were prepared in the same manner as in Example 053 or Example
054 except that the tert-butyl
4-[(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-
piperidin-1-yl)methyl]piperidine-1-carboxylate of Example 053 or
the tert-butyl
3-[(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-
piperidin-1-yl)methyl]azetidine-1-carboxylate of Example 054 was
replaced with the corresponding starting compound.
##STR00141##
Wherein Q means each cyclic amino structure shown in the following
table, HX means hydrochloric acid or trifluoroacetic acid, and the
Boc group is attached to the nitrogen atom in the cyclic amine of
Q.
TABLE-US-00023 TABLE 23 Compound Ex. R.sup.3 R.sup.6 R.sup.7 Q Name
LC-MS, m/z 055 Et H H ##STR00142## 3-ethyl-1-(5-{1-[2-
(piperidin-4- yl)ethyl]piperidin-4- yl}-1,2,4-oxadiazol-
3-yl)-1H-indazole bis(trifluoroacetate) LC-MS, m/z; 409 [M + H]+
056 Et H H ##STR00143## 3-ethyl-1-{5-[1- (piperidin-4-
ylmethyl)piperidin-4- yl]-1,2,4-oxadiazol- 3-yl}-1H-indazole
bis(trifluoroacetate) LC-MS, m/z; 395 [M + H]+ 057 Et F H
3-ethyl-6-fluoro-1- LC-MS, m/z; {5-[1-(piperidin-4- 413 [M + H]+
ylmethyl)piperidin-4- yl]-1,2,4-oxadiazol- 3-yl}-1H-indazole
dihydrochloride 058 Et H F ##STR00144## 3-ethyl-7-fluoro-1-
{5-[1-(piperidin-4- ylmethyl)piperidin-4- yl]-1,2,4-oxadiazol-
3-yl}-1H-indazole dihydrochloride LC-MS, m/z; 413 [M + H]+ 059 Et H
H ##STR00145## 3-ethyl-1-(5-{1- [(2S)-pyrrolidin-2-
ylmethyl]piperidin-4- yl}-1,2,4-oxadiazol- 3-yl)-1H-indazole
bis(trifluoroacetate) LC-MS, m/z; 381 [M + H]+ 060 Me F H
6-fluoro-3-methyl-1- LC-MS, m/z; (5-{1-[(2S)- 385 [M + H]+
pyrrolidin-2- ylmethyl]piperidin-4- yl}-1,2,4-oxadiazol-
3-yl)-1H-indazole bis(trifluoroacetate) 061 Et F H
3-ethyl-6-fluoro-1- LC-MS, m/z; (5-{1-[(2S)- 399 [M + H]+
pyrrolidin-2- ylmethyl]piperidin-4- yl}-1,2,4-oxadiazol-
3-yl)-1H-indazole bis(trifluoroacetate) 062 Et H F
3-ethyl-7-fluoro-1- LC-MS, m/z; (5-{1-[(2S)- 399 [M + H]+
pyrrolidin-2- ylmethyl]piperidin-4- yl}-1,2,4-oxadiazol-
3-yl)-1H-indazole dihydrochloride 063 .sup.iPr H F
7-fluoro-3-(propan-2- LC-MS, m/z; yl)-1-(5-{1-[(2S)- 413 [M + H]+
pyrrolidin-2- ylmethyl]piperidin-4- yl}-1,2,4-oxadiazol-
3-yl)-1H-indazole dihydrochloride 064 Et H H ##STR00146##
3-ethyl-1-(5-{1- [(2R)-pyrrolidin-2- ylmethyl]piperidin-4-
yl}-1,2,4-oxadiazol- 3-yl)-1H-indazole bis(trifluoroacetate) LC-MS,
m/z; 381 [M + H]+ 065 Et H F 3-ethyl-7-fluoro-1- LC-MS, m/z;
(5-{1-[(2R)- 399 [M + H]+ pyrrolidin-2- ylmethyl]piperidin-4-
yl}-1,2,4-oxadiazol- 3-yl)-1H-indazole dihydrochloride 066 Et H H
##STR00147## 3-ethyl-1-(5-{1- [(3R)-pyrrolidin-3-
ylmethyl]piperidin-4- yl}-1,2,4-oxadiazol- 3-yl)-1H-indazole
bis(trifluoroacetate) LC-MS, m/z; 381 [M + H]+ 067 Et H F
3-ethyl-7-fluoro-1- LC-MS, m/z; (5-{1-[(3R)- 399 [M + H]+
pyrrolidin-3- ylmethyl]piperidin-4- yl}-1,2,4-oxadiazol-
3-yl)-1H-indazole dihydrochloride 068 Et F H 3-ethyl-6-fluoro-1-
LC-MS, m/z; (5-{1-[(3R)- 399 [M + H]+ pyrrolidin-3-
ylmethyl]piperidin-4- yl}-1,2,4-oxadiazol- 3-yl)-1H-indazole
dihydrochloride 069 .sup.iPr H F 7-fluoro-3-(propan-2- LC-MS, m/z;
yl)-1-(5-{1-[(3R)- 413 [M + H]+ pyrrolidin-3- ylmethyl]piperidin-4-
yl}-1,2,4-oxadiazol- 3-yl)-1H-indazole dihydrochloride 070 Et H H
##STR00148## 3-ethyl-1-(5-{1- [(3S)-pyrrolidin-3-
ylmethyl]piperidin-4- yl}-1,2,4-oxadiazol- 3-yl)-1H-indazole
bis(trifluoroacetate) LC-MS, m/z; 381 [M + H]+ 071 Et H F
3-ethyl-7-fluoro-1- LC-MS, m/z; (5-{1-[(3S)- 399 [M + H]+
pyrrolidin-3- ylmethyl]piperidin-4- yl}-1,2,4-oxadiazol-
3-yl)-1H-indazole dihydrochloride 072 Et F H 3-ethyl-6-fluoro-1-
LC-MS, m/z; (5-{1-[(3S)- 399 [M + H]+ pyrrolidin-3-
ylmethyl]piperidin-4- yl}-1,2,4-oxadiazol- 3-yl)-1H-indazole
dihydrochloride 073 .sup.iPr H F 7-fluoro-3-(propan-2- LC-MS, m/z;
yl)-1-(5-{1-[(3S)- 413 [M + H]+ pyrrolidin-3- ylmethyl]piperidin-4-
yl}-1,2,4-oxadiazol- 3-yl)-1H-indazole dihydrochloride 074 Et F H
##STR00149## 1-{5-[1-(azetidin-3- ylmethyl)piperidin-4-
yl]-1,2,4-oxadiazol- 3-yl}-3-ethyl-6- fluoro-1H-indazole
bis(trifluoroacetate) LC-MS, m/z; 385 [M + H]+ 075 Et H F
1-{5-[1-(azetidin-3- LC-MS, m/z; ylmethyl)piperidin-4- 385 [M + H]+
yl]-1,2,4-oxadiazol- 3-yl}-3-ethyl-7- fluoro-1H-indazole
bis(trifluoroacetate) 076 Et H H ##STR00150## 4-[3-(3-ethyl-1H-
indazol-1-yl)-1,2,4- oxadiazol-5-yl]-1,4'- bipiperidine
bis(trifluoroacetate) LC-MS, m/z; 381 [M + H]+ 077 Et F H
4-[3-(3-ethyl-6- LC-MS, m/z; fluoro-1H-indazol-1- 399 [M + H]+
yl)-1,2,4-oxadiazol- 5-yl]-1,4'- bipiperidine dihydrochloride 078
Et H F 4-[3-(3-ethyl-7- LC-MS, m/z; fluoro-1H-indazol-1- 399 [M +
H]+ yl)-1,2,4-oxadiazol- 5-yl]-1,4'- bipiperidine
bis(trifluoroacetate) 079 .sup.iPr H F 4-{3-[7-fluoro-3- LC-MS,
m/z; (propan-2-yl)-1H- 413 [M + H]+ indazol-1-yl]-1,2,4-
oxadiazol-5-yl}-1,4'- bipiperidine dihydrochloride 080 Et H Cl
4-[3-(7-chloro-3- LC-MS, m/z; ethyl-1H-indazol-1- 415 [M + H]+
yl)-1,2,4-oxadiazol- 5-yl]-1,4'- bipiperidine dihydrochloride
Example 081
Preparation of
3-ethyl-1-{5-[1-(piperidin-4-yl)azetidin-3-yl]-1,2,4-oxadiazol-3-yl}-1H-i-
ndazole bis(trifluoroacetate)
##STR00151##
[0687] The title compound was prepared in the same manner as in
Example 054 except that the tert-butyl
3-[(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-
piperidin-1-yl)methyl]azetidine-1-carboxylate was replaced with
tert-butyl
4-{3-[3-(3-ethyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]azetidin-1-yl}pipe-
ridine-1-carboxylate.
[0688] LC-MS, m/z; 353 [M+H]+
Example 082
Preparation of
3-{4-[3-(3-methyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}pr-
opan-1-amine bis(trifluoroacetate)
##STR00152##
[0690] (1)
Tert-butyl(3-{4-[3-(3-methyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-
-yl]piperidin-1-yl}propyl)carbamate was prepared in the same manner
as in Example 023 except that the
3-ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and tert-butyl
4-(2-iodoethyl)piperidine-1-carboxylate were replaced with
3-methyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
hydrochloride and tert-butyl(3-bromopropyl)carbamate,
respectively.
[0691] LC-MS, m/z; 441 [M+H]+.
[0692] (2) The title compound was prepared in the same manner as in
Example 054 except that the tert-butyl
3-[(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-
piperidin-1-yl)methyl]azetidine-1-carboxylate was replaced with the
above compound.
[0693] LC-MS, m/z; 341 [M+H]+
[0694] The following compounds in the table (i.e. Examples 083 to
084) were prepared in the same manner as in Example 082 (or
replacing the trifluoroacetic acid with 4 N HCl/dioxane) except
that the
3-methyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
hydrochloride and tert-butyl(3-bromopropyl)carbamate were replaced
with the corresponding starting compound and tert-butyl
2-bromoethylcarbamate, respectively.
##STR00153##
[0695] Wherein HX is hydrochloric acid or trifluoroacetic acid.
TABLE-US-00024 TABLE 24 Ex. R.sup.3 R.sup.6 Compound Name LC-MS,
m/z 083 Me H 2-{4-[3-(3-methyl-1H-indazol-1- LC-MS, m/z;
yl)-1,2,4-oxadiazol-5- 327 [M + H]+ yl]piperidin-1-yl}ethanamine
bis(trifluoroacetate) 084 Et F 2-{4-[3-(3-ethyl-6-fluoro-1H- LC-MS,
m/z; indazol-1-yl)-1,2,4-oxadiazol-5- 359 [M + H]+
yl]piperidin-1-yl}ethanamine dihydrochloride
Example 085
Preparation of
1-{5-[1-(3-methoxypropyl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}-3-(propan--
2-yl)-1H-indazole
##STR00154##
[0697]
1-[5-(Piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-3-(propan-2-yl)-1H-inda-
zole hydrochloride (174 mg) was suspended in DMF (3 ml). To the
suspension were added 1-bromo-3-methoxy propane (92 mg), potassium
carbonate (138 mg) and sodium iodide (15 mg), and the mixture was
stirred at 60.degree. C. for 1.5 hours and then cooled to room
temperature. To the reaction mixture was added water, and the
mixture was extracted with chloroform. The organic layer was dried
over sodium sulfate and filtered, and the filtrate was concentrated
under reduced pressure. The residue was purified by silica-gel
chromatography (column; Hi-Flash.TM. Column, developing solvent:
hexane/ethyl acetate=1/1 then chloroform/methanol=9/1) to give the
title compound (145 mg) as a colorless solid.
[0698] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.52 (6H, d, J=7.0 Hz),
1.74-1.85 (2H, m), 2.03-2.22 (6H, m), 2.42-2.49 (2H, m), 2.96-3.10
(3H, m), 3.35 (3H, s), 3.44 (2H, t, J=6.4 Hz), 3.47-3.57 (1H, m),
7.28-7.34 (1H, m), 7.52-7.58 (1H, m), 7.80-7.85 (1H, m), 8.27-8.32
(1H, m).
[0699] LC-MS, m/z; 384 [M+H]+.
[0700] The compounds in the following table (i.e. Examples 086 to
095) were prepared in the same manner as in Example 085 except that
the
1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-3-(propan-2-yl)-1H-indazole
hydrochloride was replaced with the corresponding starting
compound. In order to obtain each of the trifluoroacetates in the
following table, the crude product was isolated/purified by reverse
phase HPLC.
TABLE-US-00025 TABLE 25 Chemical Ex. structure Compound Name
.sup.1H-NMR/LC-MS, m/z 086 ##STR00155## 3-chloro-1-{5-[1-
(3-methoxy- propyl)piper- idin-4-yl]-1,2,4- oxadiazol-3-yl}-
1H-indazole .sup.1H-NMR (CDCl.sub.3) .delta.: 1.74- 1.85 (2H, m),
2.02-2.24 (6H, m), 2.42-2.50 (2H, m), 2.95-3.11 (3H, m), 3.35 (3H,
s), 3.44 (2H, t, J = 6.4 Hz), 7.39- 7.45 (1H, m), 7.62-7.68 (1H,
m), 7.75-7.80 (1H, m), 8.28-8.32 (1H, m). LC-MS, m/z; 376 [M + H] +
087 ##STR00156## 3-ethyl-1-{5-[1- (3-methoxy- propyl)piper-
idin-4-yl]-1,2,4- oxadiazol-3-yl}- 1H-indazole trifluoroacetate
LC-MS, m/z; 370 [M + H] + 088 ##STR00157## 3-cyclopropyl-1-
{5-[1-(3-methoxy- propyl)piper- idin-4-yl]-1,2,4- oxadiazol-3-yl}-
1H-indazole trifluoroacetate LC-MS, m/z; 382 [M + H] + 089
##STR00158## 3-bromo-1-{5-[1- (3-methoxy- propyl)piper-
idin-4-yl]-1,2,4- oxadiazol-3-yl}- 1H-indazole LC-MS, m/z; 420 [M +
H] + 090 ##STR00159## 3-ethyl-1-{5-[1- (3-methoxy- propyl)azeti-
din-3-yl]-1,2,4- oxadiazol-3-yl}- 1H-indazole LC-MS, m/z; 342 [M +
H] + 091 ##STR00160## 3-ethyl-5-fluoro- 1-{5-[1-(3-methoxy-
propyl)piper- idin-4-yl]-1,2,4- oxadiazol-3-yl}- 1H-indazole
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.43 (3H, t, J = 8.0 Hz),
1.75-1.84 (2H, m), 1.99- 2.23 (6H, m), 2.46 (2H, t, J = 7.4 Hz),
2.96- 3.10 (5H, m), 3.34 (3H, s), 3.44 (2H, t, J = 6.3 Hz), 7.31
(1H, td, J = 8.9, 2.4 Hz), 7.38 (1H, dd, J = 8.0, 2.4 Hz), 8.24
(1H, dd, J = 9.1,4.3 Hz). LC-MS, m/z; 388 [M + H] + 092
##STR00161## 3-ethyl-6-fluoro- 1-{5-[1-(3- methoxypropyl)piper-
idin-4-yl]-1,2,4- oxadiazol-3-yl}- 1H-indazole .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.44 (3H, t, J = 7.7 Hz), 1.70-1.85 (2H, m),
1.98- 2.22 (6H, m), 2.40-2.49 (2H, m), 2.93-3.10 (5H, m), 3.35 (3H,
s), 3.44 (2H, t, J = 6.3 Hz), 7.08 (1H, td, J = 8.8, 2.2 Hz), 7.69
(1H, dd, J = 8.7, 5.0 Hz), 7.98 (1H, dd, J = 9.3, 1.7 Hz). LC-MS,
m/z; 388 [M + H] + 093 ##STR00162## 3-ethyl-4-fluoro- 1-{5-[1-(3-
methoxypropyl)piper- idin-4-yl]-1,2,4- oxadiazol-3-yl}- 1H-indazole
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.43 (3H, t, J = 7.6 Hz),
1.73-1.84 (2H, m), 1.98- 2.22 (6H, m), 2.46 (2H, t, J = 7.4 Hz),
2.95- 3.09 (3H, m), 3.15 (2H, q, J = 7.6 Hz), 3.34 (3H, s), 3.44
(2H, t, J = 6.5 Hz), 6.95 (1H, dd, J = 10.0, 7.8 Hz), 7.49 (1H, td,
J = 8.2, 5.0 Hz), 8.06 (1H, d, J = 8.5 Hz). LC-MS, m/z; 388 [M + H]
+ 094 ##STR00163## 1-{5-[1-(3- methoxypropyl)piper-
idin-4-yl]-1,2,4- oxadiazol-3-yl}-3- (2-methylpropyl)- 1H-indazole
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.01 (6H, d, J = 6.6 Hz),
1.70-1.85 (2H, m), 2.00- 2.33 (7H, m), 2.46 (2H, t, J = 7.6 Hz),
2.90- 3.11 (5H, m), 3.35 (3H, s), 3.44 (2H, t, J = 6.5 Hz),
7.29-7.36 (1H, m), 7.51-7.60 (1H, m), 7.74 (1H, d, J = 8.0 Hz),
8.29 (1H, d, J = 8.5 Hz). LC-MS, m/z; 398 [M + H] + 095
##STR00164## 3-ethyl-7-fluoro- 1-{5-[1-(3- methoxypropyl)piper-
idin-4-yl]-1,2,4- oxadiazol-3-yl}- 1H-indazole .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.44 (3H, t, J = 7.6 Hz), 1.71-1.85 (2H, m),
1.99- 2.23 (6H, m), 2.45 (2H, t, J = 7.6 Hz), 2.93- 3.13 (5H, m),
3.34 (3H, s), 3.44 (2H, t, J = 6.5 Hz), 7.19-7.30 (2H, m),
7.50-7.56 (1H, m). LC-MS, m/z; 388 [M + H] +
Example 096
Preparation of
3-(cyclohex-1-en-1-yl)-1-{5-[1-(3-methoxypropyl)piperidin-4-yl]-1,2,4-oxa-
diazol-3-yl}-1H-indazole
##STR00165##
[0702]
3-Bromo-1-{5-[1-(3-methoxypropyl)piperidin-4-yl]-1,2,4-oxadiazol-3--
yl}-1H-indazole (80 mg) was suspended in 1,4-dioxane (4 ml) and
water (0.5 ml). To the suspension were added
2-(1-cyclohexenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (52 mg),
tetrakistriphenylphosphinepalladium (11 mg) and potassium carbonate
(79 mg), and the mixture was refluxed overnight. Then, the mixture
was cooled to room temperature, and water was added thereto. The
mixture was extracted with ethyl acetate. The organic layer was
washed with water and brine, dried over sodium sulfate, filtered,
and concentrated under reduced pressure. The residue was purified
by silica-gel chromatography (column; Hi-Flash.TM. Amino Column,
developing solvent: hexane/ethyl acetate) to give the title
compound (19 mg) as a white solid.
[0703] LC-MS, m/z; 422 [M+H]+
Example 097
Preparation of
3-ethyl-1-[5-(1-ethylpiperidin-4-yl)-1,2,4-oxadiazol-3-yl]-6-fluoro-1H-in-
dazole hydrochloride
##STR00166##
[0705]
3-Ethyl-6-fluoro-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-ind-
azole trifluoroacetate (100 mg) was suspended in
N,N-dimethylformamide (2 ml). To the suspension were added ethyl
iodide (45 mg) and potassium carbonate (133 mg), and the mixture
was refluxed overnight. The reaction solution was cooled to room
temperature and water was added thereto. The mixture was extracted
with ethyl acetate. The organic layer was washed with water and
brine, dried over sodium sulfate and filtered, and the filtrate was
concentrated under reduced pressure. The residue was purified by
silica-gel chromatography (column; Hi-Flash.TM. Amino Column,
developing solvent: hexane/ethyl acetate). The resultant compound
was dissolved in methylene chloride and treated with 1N HCl/diethyl
ether to give the title compound (35 mg) as a white solid.
[0706] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.20-1.30 (3H, m), 1.34
(3H, t, J=7.4 Hz), 2.10-2.49 (5H, m), 2.98-3.16 (6H, m), 3.60 (2H,
d, J=11.7 Hz), 7.26-7.32 (1H, m), 7.87-7.95 (1H, m), 7.99-8.05 (1H,
m), 10.17 (1H, s).
[0707] LC-MS, m/z; 344 [M+H]+
[0708] The compounds in the following table (i.e. Examples 098 to
0133) were prepared in the same manner as in Example 097 except
that the
3-ethyl-6-fluoro-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and ethyl iodide were replaced with the
corresponding starting compound and R--X which means an alkylating
agent, respectively. In order to obtain each of the
trifluoroacetates in the following table, the residue was
isolated/purified by reverse phase HPLC, and each free form of the
compounds in the following table was obtained by omitting the
conversion step into hydrochloride in Example 097.
TABLE-US-00026 TABLE 26 .sup.1H-NMR/ Compound LC-MS, Ex. R--X
Chemical structure Name m/z 098 ##STR00167## ##STR00168##
1-{5-[1-(2- methylpropyl)pi- peridin-4-yl]- 1,2,4- oxadiazol-3-
yl}-3-(propan- 2-yl)-1H- indazole trifluoroacetate LC-MS, m/z; 368
[M + H] + 099 ##STR00169## ##STR00170## 1-{5-[1- (cyclobutylmeth-
yl)piperidin-4- yl]-1,2,4- oxadiazol-3- yl}-3-ethyl-1H- indazole
trifluoroacetate LC-MS, m/z; 366 [M + H] + 100 ##STR00171##
##STR00172## 3-ethyl-1-{5- [1-(2- fluoroethyl)pi- peridin-4-yl]-
1,2,4- oxadiazol-3- yl}-1H-indazole LC-MS, m/z; 344 [M + H] + 101
##STR00173## ##STR00174## 1-{5-[1-(butan- 2-yl)piperidin-
4-yl]-1,2,4- oxadiazol-3- yl}-3-ethyl-1H- indazole trifluoroacetate
LC-MS, m/z; 354 [M + H] + 102 ##STR00175## ##STR00176##
1-{5-[1-(butan- 2-yl)piperidin- 4-yl]-1,2,4- oxadiazol-3- yl}-3-
cyclopropyl-1H- indazole trifluoroacetate LC-MS, m/z; 366 [M + H] +
103 ##STR00177## ##STR00178## 3-ethyl-1-(5- [1-(2- methylpropyl)pi-
peridin-4-yl]- 1,2,4- oxadiazol-3- yl}-1H-indazole LC-MS, m/z; 354
[M + H] + 104 ##STR00179## ##STR00180## 2-{4-[3-(3- ethyl-1H-
indazol-1-yl)- 1,2,4- oxadiazol-5- yl]piperidin-1- yl}-N,N-
dimethylethanamine trifluoroacetate LC-MS, m/z; 369 [M + H] + 105
##STR00181## ##STR00182## 3-ethyl-1-(5- {1-[2-(2- methylphenyl)eth-
yl]piperidin- 4-yl}-1,2,4- oxadiazol-3- yl)-1H-indazole LC-MS, m/z;
416 [M + H] + 106 ##STR00183## ##STR00184## 3-cyclopropyl-
1-{5-[1-(2- methylpropyl)pi- peridin-4-yl]- 1,2,4- oxadiazol-3-
yl}-1H-indazole LC-MS, m/z; 366 [M + H] + 107 ##STR00185##
##STR00186## 1-{5-[1- (cyclobutylmeth- yl)piperidin-4- yl]-1,2,4-
oxadiazol-3- yl}-3- cyclopropyl-1H- indazole trifluoroacetate
LC-MS, m/z; 378 [M + H] + 108 ##STR00187## ##STR00188##
N-(2-{4-[3-(3- ethyl-1H- indazol-1-yl)- 1,2,4- oxadiazol-5-
yl]piperidin-1- yl}ethyl)acetamide LC-MS, m/z; 383 [M + H] + 109
##STR00189## ##STR00190## 1-{5-[1-(butan- 2-yl)piperidin-
4-yl]-1,2,4- oxadiazol-3- yl}-3-methyl- 1H-indazole
trifluoroacetate LC-MS, m/z; 340 [M + H] + 110 ##STR00191##
##STR00192## 3-methyl-1-{5- [1-(2- methylpropyl)pi- peridin-4-yl]-
1,2,4- oxadiazol-3- yl}-1H-indazole trifluoroacetate LC-MS, m/z;
340 [M + H] + 111 ##STR00193## ##STR00194## 1-{5-[1-
(cyclobutylmeth- yl)piperidin-4- yl]-1,2,4- oxadiazol-3-
yl}-3-methyl- 1H-indazole trifluoroacetate LC-MS, m/z; 352 [M + H]
+ 112 ##STR00195## ##STR00196## 1-{5-[1- (cyclopropylmeth-
yl)piperidin- 4-yl]-1,2,4- oxadiazol-3- yl}-3-ethyl-1H- indazole
trifluoroacetate LC-MS, m/z; 352 [M + H] + 113 ##STR00197##
##STR00198## 3-ethyl-1-{5- [1-(3- methylbutyl)piper- idin-4-yl]-
1,2,4- oxadiazol-3- yl}-1H-indazole trifluoroacetate LC-MS, m/z;
368 [M + H] + 114 ##STR00199## ##STR00200## 1-{5-[1-(butan-
2-yl)piperidin- 4-yl]-1,2,4- oxadiazol-3- yl}-3- cyclobutyl-1H-
indazole trifluoroacetate LC-MS, m/z; 380 [M + H] + 115
##STR00201## ##STR00202## 3-cyclobutyl-1- {5-[1-{2-
methylpropyl)pi- peridin-4-yl]- 1,2,4- oxadiazol-3- yl}-1H-indazole
trifluoroacetate LC-MS, m/z; 380 [M + H] + 116 ##STR00203##
##STR00204## 3-ethyl-1-[5-(1- propylpiperidin- 4-yl)-1,2,4-
oxadiazol-3- yl]-1H-indazole trifluoroacetate LC-MS, m/z; 340 [M +
H] + 117 ##STR00205## ##STR00206## 3-(propan-2- yl)-1-[5-(1-
propylpiperidin- 4-yl)-1,2,4- oxadiazol-3- yl]-1H-indazole
trifluoroacetate LC-MS, m/z; 354 [M + H] + 118 ##STR00207##
##STR00208## 3-ethyl-1-{5- [1-(3- fluoropropyl)pi- peridin-4-yl]-
1,2,4- oxadiazol-3- yl}-1H-indazole trifluoroacetate LC-MS, m/z;
358 [M + H] + 119 ##STR00209## ##STR00210## 3-cyclopropyl- 1-{5-[1-
(cyclopropylmeth- yl)piperidin- 4-yl]-1,2,4- oxadiazol-3-
yl}-1H-indazole trifluoroacetate LC-MS, m/z; 364 [M + H] + 120
##STR00211## ##STR00212## 3-cyclopropyl- 1-{5-[1-(3-
methylbutyl)piper- idin-4-yl]- 1,2,4- oxadiazol-3- yl}-1H-indazole
trifluoroacetate LC-MS, m/z; 380 [M + H] + 121 ##STR00213##
##STR00214## 3-cyclopropyl- 1-{5-[1-(3- fluoropropyl)pi-
peridin-4-yl]- 1,2,4- oxadiazol-3- yl}-1H-indazole trifluoroacetate
LC-MS, m/z; 370 [M + H] + 122 ##STR00215## ##STR00216##
3-cyclopropyl- 1-[5-(1- propylpiperidin- 4-yl)-1,2,4- oxadiazol-3-
yl]-1H-indazole trifluoroacetate LC-MS, m/z; 352 [M + H] + 123
##STR00217## ##STR00218## 3-ethyl-1-(5- {1-[2- (tetrahydro-2H-
pyran-4- yl)ethyl]piper- idin-4-yl}- 1,2,4- oxadiazol-3-
yl)-1H-indazole LC-MS, m/z; 410 [M + H] + 124 ##STR00219##
##STR00220## 3-(propan-2- yl)-1-(5-{1-[2- (tetrahydro-2H- pyran-4-
yl)ethyl]piper- idin-4-yl}- 1,2,4- oxadiazol-3- yl)-1H-indazole
LC-MS, m/z; 424 [M + H] + 125 ##STR00221## ##STR00222##
3-cyclopropyl- 1-(5-{1-[2- (tetrahydro-2H- pyran-4- yl)ethyl]piper-
idin-4-yl}- 1,2,4- oxadiazol-3- yl)-1H-indazole LC-MS, m/z; 422 [M
+ H] + 126 ##STR00223## ##STR00224## 3-cyclobutyl-1- (5-{1-[2-
(tetrahydro-2H- pyran-4- yl)ethyl]piper- idin-4-yl}- 1,2,4-
oxadiazol-3- yl)-1H-indazole LC-MS, m/z; 436 [M + H] + 127
##STR00225## ##STR00226## tert-butyl (2- {4-[3-(3- methyl-1H-
indazol-1-yl)- 1,2,4- oxadiazol-5- yl]piperidin-1-
yl}ethyl)carbamate .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.37 (9H,
s), 1.83 (2H, q, J = 10.7 Hz), 2.05-2.17 (4H, m), 2.34 (2H, t, J =
7.0 Hz), 2.60 (3H, s), 2.84- 2.91 (2H, m), 3.01- 3.15 (3H, m), 6.66
(1H, t, J = 5.0 Hz), 7.39 = (1H, t, J 7.6 Hz), 7.64 (1H, t, J = 7.7
Hz), 7.91 (1H, d, J = 8.0 Hz), 8.20 (1H, d, J = 8.5 Hz). LC-MS,
m/z; 427 [M + H] + 128 ##STR00227## ##STR00228## 3-ethyl-1-(5-
{1-[2- (tetrahydrofuran-2- yl)ethyl]piper- idin-4-yl}- 1,2,4-
oxadiazol-3- yl)-1H-indazole .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.33- 1.43 (4H, m), 1.62 (2H, q, J = 7.0 Hz), 1.74-1.98 (5.0H, m),
2.12 (3H, d, J = 11.7 Hz), 2.91-2.96 (1H, m), 3.03 (2H, q, J = 7.6
Hz), 3.12-3.20 (1H, m), 3.31-3.34 (2H, m), 3.43-3.50 (2H, m),
3.53-3.59 (1H, m), 3.69-3.76 (2H, m), 7.38 (1H, m), 7.64 (1H, m),
7.94 (1H, d, J = 8.0 Hz), 8.20 (1H, d, J = 8.5 Hz). LC-MS, m/z; 396
[M + H] + 129 ##STR00229## ##STR00230## 3-ethyl-1-(5- {1-[2-
(tetrahydro-2H- pyran-2- yl)ethyl]piper- idin-4-yl}- 1,2,4-
oxadiazol-3- yl)-1H-indazole LC-MS, m/z; 410 [M + H] + 130
##STR00231## ##STR00232## 3-ethyl-1-{5- [1-(tetrahydro- 2H-pyran-3-
ylmethyl)piper- idin-4-yl]- 1,2,4- oxadiazol-3- yl}-1H-indazole
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.10- 1.21 (1H, m), 1.35 (3H,
t, J = 7.6 Hz), 1.40- 1.58 (2H, m), 1.71-1.94 (4H, m), 2.07-2.38
(4H, m), 2.78-3.20 (6H, m), 3.25-3.31 (1H, m), 3.69-3.82 (4H, m),
7.36-7.40 (1H, m), 7.61-7.66 (1H, m), 7.93 (1H, d, J = 8.0 Hz),
8.19 (1H, d, J = 8.5 Hz). LC-MS, m/z; 396 [M + H] + 131
##STR00233## ##STR00234## 3-ethyl-6- fluoro-1-(5-{1-[2-
(tetrahydrofuran-2- yl)ethyl]piper- idin-4-yl}- 1,2,4- oxadiazol-3-
yl)-1H-indazole .sup.1H-NMR (CDCl.sub.3) .delta.: 1.36-1.57 (4H,
m), 1.64-2.25 (11H, m), 2.39-2.60 (2H, m), 2.95-3.16 (5H, m),
3.67-3.94 (3H, m), 7.08 (1H, td, J = 8.8, 2.2 Hz), 7.69 (1H, dd, J
= 8.7, 5.0 Hz), 7.98 (1H, dd, J = 9.5, 2.2 Hz). LC-MS, m/z; 414 [M
+ H] + 132 ##STR00235## ##STR00236## 3-ethyl-1-{5-
[1-(tetrahydrofuran- 2-ylmethyl)piper- idin-4-yl]- 1,2,4-
oxadiazol-3- yl}-1H-indazole LC-MS, m/z; 382 [M + H] + 133
##STR00237## ##STR00238## 7-fluoro-3- (propan-2-yl)- 1-{5-[1-
(propan-2- yl)piperidin-4- yl]-1,2,4- oxadiazol-3- yl}-1H-indazole
hydrochloride .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.31 (6H, d, J =
6.6Hz), 1.41 (6H, d, J = 7.1 Hz), 2.24-2.43 (4H, m), 3.08-3.21 (2H,
m), 3.42-3.59 (5H, m), 7.35-7.43 (1H, m), 7.44-7.52 (1H, m),
7.81-7.89 (1H, m), 10.60- 10.85 (1H, m). LC-MS, m/z; 372 [M + H]
+
Example 134
Preparation of
3-ethyl-6-fluoro-1-{5-[1-(tetrahydro-2H-pyran-4-ylmethyl)piperidin-4-yl]--
1,2,4-oxadiazol-3-yl}-1H-indazole
##STR00239##
[0710]
3-Ethyl-6-fluoro-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-ind-
azole trifluoroacetate (150 mg) was dissolved in dichloromethane (3
ml), and to the solution was added tetrahydropyrane-4-carboaldehyde
(60 mg) and triacetoxysodium borohydride (222 mg). The mixed
solution was stirred at room temperature for 3 hours. To the
reaction solution was added saturated sodium bicarbonate aqueous
solution (10 ml). The mixture was extracted with ethyl acetate (20
ml), and the organic layer was again washed with water (10
ml.times.2). The organic layer was dried over sodium sulfate and
filtered, and the filtrate was concentrated under reduced pressure.
The residue was purified by silica-gel chromatography (column;
Hi-Flash.TM. Amino Column, developing solvent: hexane/ethyl
acetate=2:1) to give the title compound (84 mg) as a white
solid.
[0711] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.27 (2H, ddd, J=24.9,
11.9, 4.2 Hz), 1.44 (3H, t, J=8.0 Hz), 1.63-1.83 (3H, m), 1.99-2.18
(6H, m), 2.22 (2H, d, J=7.1 Hz), 2.89-3.11 (5H, m), 3.40 (2H, t,
J=10.9 Hz), 3.98 (2H, dd, J=11.3, 3.5 Hz), 7.08 (1H, td, J=8.8, 2.3
Hz), 7.70 (1H, dd, J=8.7, 5.0 Hz), 7.98 (1H, dd, J=9.4, 2.1
Hz).
[0712] LC-MS, m/z; 414 [M+H].sup.+.
[0713] The compounds in the following table (i.e. Examples 135 to
159) were prepared in the same manner as in Example 134 except that
the
3-ethyl-6-fluoro-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and tetrahydropyrane-4-carboaldehyde were replaced
with the corresponding starting compound and aldehyde or ketone,
respectively. Each of the hydrochloride compounds in the following
table was obtained by dissolving the resultant compound in
methylene chloride and treating with 1N HCl/diethyl ether
solution.
TABLE-US-00027 TABLE 27 Chemical .sup.1H-NMR/ Ex. structure
Compound Name LC-MS, m/z 135.sup.1) ##STR00240## 3-ethyl-1-{5-[1-
(tetrahydro-2H- pyran-4- yl)piperidin-4-yl]- 1,2,4-oxadiazol-3-
yl}-1H-indazole LC-MS, m/z; 382 [M + H] + 136 ##STR00241##
3-ethyl-1-{5-[1- (tetrahydrofuran-3- yl)piperidin-4-yl]-
1,2,4-oxadiazol-3- yl}-1H-indazole LC-MS, m/z; 368 [M + H] + 137
##STR00242## 3-ethyl-6-fluoro-1- (5-{1-[2- (tetrahydro-2H- pyran-4-
yl)ethyl]piperidin- 4-yl}-1,2,4- oxadiazol-3-yl)-1H- indazole
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.25-1.68 (10H, m), 2.01-2.25
(6H, m), 2.41 (2H, t, J = 7.7 Hz), 2.93-3.14 (5H, m), 3.34- 3.46
(2H, m), 3.96 (2H, dd, J = 11.1, 4.0 Hz), 7.08 (1H, td, J = 8.8,
2.2 Hz), 7.70 (1H, dd, J = 8.8, 5.1 Hz), 7.98 (1H, dd, J = 9.3, 2.2
Hz). LC-MS, m/z; 428 [M + H] + 138 ##STR00243## 3-ethyl-6-fluoro-1-
{5-[1- (tetrahydrofuran-3- yl)piperidin-4-yl]- 1,2,4-oxadiazol-3-
yl}-1H-indazole .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (3H, t, J =
7.6 Hz), 1.83- 1.95 (1H, m), 2.01-2.36 (7H, m), 2.81-2.91 (1H, m),
2.98- 3.15 (5H, m), 3.67 (1H, dd, J = 8.7, 7.0 Hz), 3.81 (1H, dd, J
= 15.9, 8.3 Hz), 3.88-4.02 (2H, m), 7.08 (1H, td, J = 8.9, 2.2 Hz),
7.70 (1H, dd, J = 8.8, 5.1 Hz), 7.97 (1H, dd, J = 9.3, 2.2 Hz).
LC-MS, m/z; 386 [M + H] + 139 ##STR00244## 3-ethyl-6-methoxy-
1-{5-[1- (tetrahydro-2H- pyran-4- ylmethyl)piperidin- 4-yl]-1,2,4-
oxadiazol-3-yl}-1H- indazole .sup.1H-NMR (CDCl.sub.3) .delta.: 1.27
(2H, ddd, J = 24.9, 12.0, 4.4 Hz), 1.42 (3H, t, J = 7.7 Hz),
1.62-1.82 (3H, m), 1.98- 2.25 (8H, m), 2.89-2.98 (2H, m), 3.04 (3H,
q, J = 7.6 Hz), 3.34-3.45 (2H, m), 3.91-4.02 (5H, m), 6.94 (1H, dd,
J = 8.8, 2.2 Hz), 7.60 (1H, d, J = 8.8 Hz), 7.71 (1H, d, J = 2.0
Hz). LC-MS, m/z; 426 [M + H] + 140 ##STR00245## 3-ethyl-7-fluoro-1-
{5-[1-{tetrahydro- 2H-pyran-4- ylmethyl)piperidin- 4-yl]-1,2,4-
oxadiazol-3-yl}-1H- indazole hydrochloride .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 1.15-1.32 (2H, m), 1.36 (3H, t, J = 7.4
Hz), 1.71-1.83 (2H, m), 2.01- 2.20 (1H, m), 2.26-2.54 (4H, m),
2.93-3.19 (6H, m), 3.25- 3.55 (3H, m), 3.59-3.74 (2H, m), 3.79-3.91
(2H, m), 7.35- 7.53 (2H, m), 7.76-7.84 (1H; m), 10.40-10.65 (1H,
m). LC-MS, m/z; 414 [M + H] + 141 ##STR00246## 3-ethyl-6-fluoro-1-
{5-[1-(tetrahydro- 2H-pyran-4- yl)piperidin-4-yl]-
1,2,4-oxadiazol-3- yl}-1H-indazole LC-MS, m/z; 400 [M + H] + 142
##STR00247## 3-ethyl-7-fluoro-1- {5-[1-(tetrahydro- 2H-pyran-4-
yl)piperidin-4-yl]- 1,2,4-oxadiazol-3- yl}-1H-indazole LC-MS, m/z;
400 [M + H] + 143 ##STR00248## 3-ethyl-6-fluoro-1- {5-[1-(propan-2-
yl)piperidin-4-yl]- 1,2,4-oxadiazol-3- yl}-1H-indazole .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 0.97 (6H, d, J = 6.6 Hz), 1.34 (3H, t, J =
7.5 Hz), 1.72- 1.86 (2H, m), 2.05-2.15 (2H, m), 2.29 (2H, t, J =
10.5 Hz), 2.68-2.87 (3H, m), 2.97-3.13 (3H, m), 7.22- 7.30 (1H, m),
7.85-7.90 (1H, m), 7.95-8.02 (1H, m). LC-MS, m/z; 358 [M + H] + 144
##STR00249## 3-ethyl-1-{5-[1- (propan-2- yl)piperidin-4-yl]-
1,2,4-oxadiazol-3- yl}-1H-indazole .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 0.97 (6H, d, J = 6.6 Hz), 1.35 (3H, t, J = 7.5 Hz), 1.72-
1.87 (2H, m), 2.06 -2.14 (2H, m), 2.28 (2H, t, J = 10.5 Hz),
2.65-2.78 (1H, m), 2.83 (2H, d, J = 11.6 Hz), 2.98-3.14 (3H, m),
7.37 (1H, t, J = 7.5 Hz), 7.63 (1H, t, J = 7.7 Hz), 7.92 (1H, d, J
= 7.9 Hz), 8.19 (1H, d, J = 8.4 Hz). LC-MS, m/z; 340 [M + H] + 145
##STR00250## 3-ethyl-7-fluoro-1- (5-{1-[2- (tetrahydro-2H- pyran-4-
yl)ethyl]piperidin- 4-yl}-1,2,4- oxadiazol-3-yl)-1H- indazole
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.24-1.68 (10H, m), 2.00-2.25
(6H, m), 2.40 (2H, t, J = 7.7 Hz), 2.91-3.16 (5H, m), 3.32- 3.47
(2H, m), 3.95 (2H, dd, J = 11.3, 3.8 Hz), 7.19-7.31 (2H, m),
7.50-7.57 (1H, m). LC-MS, m/z; 428 [M + H] + 146 ##STR00251##
3-ethyl-7-fluoro-1- {5-[1- (tetrahydrofuran-3- yl)piperidin-4-yl]-
1,2,4-oxadiazol-3- yl}-1H-indazole .sup.1H-NMR (CDCl.sub.3)
.delta.: 1.44 (3H, t, J = 7.6 Hz), 1.81- 1.96 (1H, m), 1.99-2.36
(7H, m), 2.80-2.90 (1H, m), 2.97- 3.16 (5H, m), 3.66 (1H, t, J =
7.8 Hz), 3.80 (1H, dd, J = 16.1, 8.0 Hz), 3.88-4.02 (2H, m),
7.20-7.33 (2H, m), 7.50- 7.59 (1H, m). LC-MS, m/z; 386 [M + H] +
147 ##STR00252## 3-(methoxymethyl)- 1-{5-[1- (tetrahydro-2H-
pyran-4- yl)piperidin-4-yl]- 1,2,4-oxadiazol-3- yl}-1H-indazole
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.55-1.82 (6H, m), 1.99-2.14 (2H,
m), 2.17- 2.27 (2H, m), 2.32-2.43 (2H, m), 2.47-2.59 (1H, m), 2.99-
3.12 (3H, m), 3.34-3.49 (5H, m), 4.05 (2H, dd, J = 11.1, 4.3 Hz),
7.36 (1H, t, J = 7.6 Hz), 7.59 (1H, t, J = 7.8 Hz), 7.96 (1H, d, J
= 8.0 Hz), 8.30 (1H, d, J = 8.5 Hz). LC-MS, m/z; 398 [M + H] + 148
##STR00253## 3-ethyl-6-fluoro-1- {5-[1-(oxetan-3-
yl)piperidin-4-yl]- 1,2,4-oxadiazol-3- yl}-1H-indazole LC-MS, m/z;
372 [M + H] + 149 ##STR00254## 3-(difluoromethyl)- 1-{5-[1-
(tetrahydro-2H- pyran-4- ylmethyl)piperidin- 4-yl]-1,2,4-
oxadiazol-3-yl}-1H- indazole .sup.1H-NMR (CDCl.sub.3) .delta.: 1.27
(2H, ddd, J = 24.4, 12.3, 4.0 Hz), 1.56- 1.86 (4H, m), 1.98-2.32
(8H, m), 2.87-3.13 (3H, m), 3.40 (2H, t, J = 11.7 Hz), 3.98 (2H,
dd, J = 11.6, 3.3 Hz), 7.45 (1H, t, J = 7.5 Hz), 7.66 (1H, dd, J =
8.4, 7.3 Hz), 8.03 (1H, d, J = 8.1 Hz), 8.36 (1H, d, J = 4.3 Hz).
LC-MS, m/z; 418 [M + H] +. 150 ##STR00255## 7-fluoro-3-(propan-
2-yl)-1-{5-[1- (tetrahydro-2H- pyran-4- yl)piperidin-4-yl]-
1,2,4-oxadiazol-3- yl}-1H-indazole hydrochloride .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 1.41 (6H, d, J = 6.8 Hz), 1.67-1.84 (2H,
m), 1.97-2.11 (2H, m), 2.23- 2.47 (4H, m), 3.05-3.68 (9H, m),
3.92-4.06 (2H, m), 7.34- 7.53 (2H, m), 7.80-7.88 (1H, m),
10.89-11.09 (1H, m). LC-MS, m/z; 414 [M + H] + . 151 ##STR00256##
1-[5-(1-cyclobutyl piperidin-4-yl)- 1,2,4-oxadiazol-3-
yl]-3-ethyl-7- fluoro-1H-indazole .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 1.34 (3H, t, J = 7.6 Hz), 1.57-1.65 (2H, m), 1.72-1.81
(4H, m), 1.87- 1.99 (4H, m), 2.08 (2H, d, J = 12.0 Hz), 2.69- 2.69
(1H, m), 2.76 (2H, d, J = 11.3 Hz), 3.03 (2H, q, J = 7.6 Hz),
3.11-3.13 (1H, m), 7.34- 7.39 (1H, m), 7.41-7.48 (1H, m), 7.77 (1H,
d, J = 8.0 Hz). LC-MS, m/z; 370 [M + H] + 152 ##STR00257##
3-ethyl-7-fluoro-1- [5-(1- propylpiperidin-4- yl)-1,2,4-
oxadiazol-3-yl]-1H- indazole .sup.1H-NMR (DMSO-d.sub.6) .delta.:
0.85 (3H, t, J = 7.4 Hz), 1.34 (3H, t, J = 7.6 Hz), 1.44 (2H, m),
1.74- 1.85 (2H, m), 2.03-2.11 (4H, m), 2.24 (2H, t, J = 7.4 Hz),
2.81-2.88 (2H, m), 3.03 (2H, q, J = 7.5 Hz), 3.08-3.17 (1H, m),
7.34-7.39 (1H, m), 7.42- 7.48 (1H, m), 7.77 (1H, d, J = 8.0 Hz).
LC-MS, m/z; 358 [M + H] + 153 ##STR00258## 3-ethyl-7-fluoro-1-
{5-[1-(propan-2- yl)piperidin-4-yl]- 1,2,4-oxadiazol-3-
yl}-1H-indazole .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.97 (6H d, J =
6.4 Hz), 1.34 (3H, t, J = 7.5 Hz), 1.70- 1.84 (2H, m), 2.04-2.14
(2H, m), 2.27 (2H, t, J = 10.3 Hz), 2.66-2.86 (3H, m), 2.99-3.14
(3H, m), 7.33- 7.48 (2H, m), 7.77 (1H, d, J = 7.5 Hz). LC-MS, m/z;
358 [M + H] + 154 ##STR00259## 1-[5-(1-cyclopentyl piperidin-4-yl)-
1,2,4-oxadiazol-3- yl]-3-ethyl-7- fluoro-1H-indazole .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 1.30-1.37 (6H, m), 1.45- 1.62 (4H, m),
1.74-1.85 (4H, m), 2.05-2.15 (4H, m), 2.89- 2.96 (2H, m), 3.03 (2H,
q, J = 7.6 Hz), 3.08- 3.17 (1H, m), 7.34-7.39 (1H, m), 7.42-7.47
(1H, m), 7.77 (1H, d, J = 7.8 Hz). LC-MS, m/z; 384 [M + H] + 155
##STR00260## 7-fluoro-3-(propan- 2-yl)-1-[5-(1- propylpiperidin-4-
yl)-1,2,4- oxadiazol-3-yl]-1H- indazole .sup.1H-NMR (CDCl.sub.3)
.delta.: 0.91 (3H, t, J = 7.3 Hz), 1.45- 1.60 (8H, m), 1.99-2.23
(6H, m), 2.29-2.39 (2H, m), 2.93- 3.12 (3H, m), 3 .41-3.55 (1H, m),
7.17-7.29 (2H, m), 7.55- 7.63 (1H, m). LC-MS, m/z; 372 [M + H] +
156 ##STR00261## 1-[5-(1-cyclobutyl piperidin-4-yl)-
1,2,4-oxadiazol-3- yl]-7-fluoro-3- (propan-2-yl)-1H- indazole
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (6H, d, J = 7.0 Hz), 1.61-
2.25 (12H, m), 2.67-2.81 (1H, m), 2.86-3.12 (3H, m), 3.40- 3.56
(1H, m), 7.17-7.29 (2H, m), 7.54-7.62 (1H, m). LC-MS, m/z; 384 [M +
H] + 157 ##STR00262## 7-fluoro-3-(propan- 2-yl)-1-{5-[1-
(tetrahydro-2H- pyran-4- ylmethyl)piperidin- 4-yl]-1,2,4-
oxadiazol-3-yl}-1H- indazole hydrochloride .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 1.15-1.33 (2H, m), 1.41 (6H, d, J = 6.8
Hz), 1.69-1.83 (2H, m), 2.00- 2.20 (1H, m), 2.26-2.55 (4H, m),
2.93-3.19 (4H, m), 3.25- 3.56 (5H, m), 3.59-3.76 (1H, m), 3.78-3.93
(2H, m), 7.35- 7.52 (2H, m), 7.81-7.89 (1H, m), 10.34-10.60 (1H,
m). LC-MS, m/z; 428 [M + H] + 158 ##STR00263## 7-chloro-3-ethyl-1-
{5-[1-(tetrahydro- 2H-pyran-4- ylmethyl)piperidin- 4-yl]-1,2,4-
oxadiazol-3-yl}-1H- indazole hydrochloride .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 1.13-1.43 (5H, m), 1.71- 1.87 (2H, m),
2.02-2.19 (1H, m), 2.26-2.53 (4H, m), 2.93- 3.18 (6H, m), 3.25-3.95
(7H, m), 7.39 (1H, t, J = 7.8 Hz), 7.65-7.71 (1H, m), 7.93-8.03
(1H, m), 10.47- 10.74 (1H, m). LC-MS, m/z; 430 [M + H] +
.sup.1)Titanium tetraisopropoxide was added to the reaction
system.
Example 159
Preparation of
3-ethyl-1-[5-(1-propylazetidin-3-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate
##STR00264##
[0715]
1-[5-(Azetidin-3-yl)-1,2,4-oxadiazol-3-yl]-3-ethyl-1H-indazole
hydrochloride (100 mg) was suspended in acetonitrile (4 ml). To the
suspension were added propyl bromide (48 mg), potassium carbonate
(272 mg) and sodium iodide (10 mg), and the mixture was stirred at
room temperature overnight. After the reaction was completed, water
was added to the reaction solution, and the mixture was extracted
with ethyl acetate. The organic layer was washed with water and
brine, dried over sodium sulfate and filtered, and the filtrate was
concentrated under reduced pressure. The residue was purified by
reverse phase HPLC to give the title compound (20 mg) as a
pale-yellow oil.
[0716] LC-MS, m/z; 312 [M+H]+
[0717] The compounds in the following table (i.e. Examples 160 to
165) were prepared in the same manner as in Example 159 except that
the 1-[5-(azetidin-3-yl)-1,2,4-oxadiazol-3-yl]-3-ethyl-1H-indazole
hydrochloride and propyl bromide were replaced with the
corresponding starting compound. In the following table, R--X means
an alkylating agent.
TABLE-US-00028 TABLE 28 Chemical .sup.1H-NMR/ Ex. R--X structure
Compound Name LC-MS, m/z 160 ##STR00265## ##STR00266##
1-{5-[1-(butan-2- yl)azetidin-3- yl]-1,2,4- oxadiazol-3-yl}-
3-ethyl-1H- indazole trifluoroacetate LC-MS, m/z; 326 [M + H] + 161
##STR00267## ##STR00268## 1-{5-[1-(butan-2- yl)azetidin-3-
yl]-1,2,4- oxadiazol-3-yl}- 3-(propan-2-yl)- 1H-indazole
trifluoroacetate LC-MS, m/z; 340 [M + H] + 162 ##STR00269##
##STR00270## methyl (2-{3-[3- (3-ethyl-6- fluoro-1H- indazol-1-yl)-
1,2,4-oxadiazol- 5-yl]azetidin-1- yl}ethyl)carbamate
trifluoroacetate LC-MS, m/z; 389 [M + H] + 163 ##STR00271##
##STR00272## methyl (2-{3-[3- (3-ethyl-1H- indazol-1-yl)-
1,2,4-oxadiazol- 5-yl]azetidin-1- yl}ethyl)carbamate
trifluoroacetate LC-MS, m/z; 371 [M + H] + 164 ##STR00273##
##STR00274## 3-ethyl-1-[5-(1- ethylazetidin-3- yl)-1,2,4-
oxadiazol-3-yl]- 1H-indazole trifluoroacetate LC-MS, m/z; 298 [M +
H] + 165 ##STR00275## ##STR00276## 3-ethyl-1-[5-(1-
ethylazetidin-3- yl)-1,2,4- oxadiazol-3-yl]- 6-fluoro-1H- indazole
trifluoroacetate LC-MS, m/z; 316 [M + H] +
Preparations of Examples 166 to 167
##STR00277##
[0719] The compounds in the following table (i.e. Examples 166 to
167) were prepared in the same manner as in Example 134 except that
the
3-ethyl-6-fluoro-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate was replaced with the corresponding starting
compound, the triacetoxysodium borohydride was replaced with sodium
cyanoborohydride, and the obtained crude-product was
isolated/purified by reverse phase HPLC.
TABLE-US-00029 TABLE 29 Chemical .sup.1H-NMR/ Ex. R.sup.6 structure
Compound Name LC-MS, m/z 166 H ##STR00278## 3-ethyl-1-{5-[1-
(tetrahydro-2H-pyran-4- yl)azetidin-3-yl]- 1,2,4-oxadiazol-3-yl}-
1H-indazole trifluoroacetate LC-MS, m/z; 354 [M + H] + 167 F
##STR00279## 3-ethyl-6-fluoro-1-{5- [1-(tetrahydro-2H-
pyran-4-yl)azetidin-3- yl]-1,2,4-oxadiazol-3- yl}-1H-indazole
trifluoroacetate LC-MS, m/z; 372 [M + H] +
Example 168
Preparation of methyl
4-(2-{4-[3-(3-ethyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}-
ethyl)piperidine-carboxylate hydrochloride
##STR00280##
[0721]
3-Ethyl-1-(5-{1-[2-(piperidin-4-yl)ethyl]piperidin-4-yl}-1,2,4-oxad-
iazol-3-yl)-1H-indazole bis(trifluoroacetate) (100 mg) was
suspended in dichloromethane (4 ml). To the suspension was added
triethylamine (38 mg), and the mixture was stirred for 5 minutes.
To the reaction mixture was added methyl chloroformate (18 mg), and
the mixed solution was stirred at room temperature overnight. After
the reaction was completed, water was added to the reaction
solution, and the mixture was extracted with ethyl acetate. The
organic layer was washed with water and brine, dried over sodium
sulfate and filtered, and the filtrate was concentrated under
reduced pressure. The residue was purified by silica-gel
chromatography (column; Hi-Flash.TM. Amino Column, developing
solvent: hexane/ethyl acetate). The resultant compound was
dissolved in methylene chloride and treated with 1N HCl/diethyl
ether to give the title compound (33 mg) as a white solid.
[0722] LC-MS, m/z; 467 [M+H]+
Example 169
Preparation of
3-ethyl-1-[5-(1-{[1-(methylsulfonyl)piperidin-3-yl]methyl}piperidin-4-yl)-
-1,2,4-oxadiazol-3-yl]-1H-indazole trifluoroacetate
##STR00281##
[0724] (1) Piperidin-3-ylmethanol (5.0 g) was dissolved in
dichloromethane (40 ml). To the solution was added triethylamine
(13.2 g), and the mixed solution was stirred at 0.degree. C. To the
reaction solution was added dropwise methanesulfonyl chloride (5.97
g) dissolved in dichloromethane (15 ml) at 0.degree. C. with
stirring, and the mixture was warmed to room temperature and
stirred for 6 hours. Water (30 ml) was added to the reaction
solution, and the mixture was extracted with dichloromethane. The
organic layer was dried over sodium sulfate and filtered, and the
filtrate was concentrated under reduced pressure to give
[1-(methylsulfonyl)piperidin-3-yl]methyl methanesulfonate.
[0725] (2)
3-Ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
hydrochloride (150 mg) was suspended in dichloromethane (4 ml). To
the suspension was added triethylamine (58 mg), and the mixture was
stirred for 5 minutes. Then the above-prepared
[1-(methylsulfonyl)piperidin-3-yl]methyl methanesulfonate (159 mg)
was added thereto, and the mixture was stirred at room temperature
overnight. After the reaction was completed, water was added to the
reaction solution, and the mixture was extracted with ethyl
acetate. The organic layer was washed with water and brine, dried
over sodium sulfate and filtered, and the filtrate was concentrated
under reduced pressure. The residue was purified by reverse phase.
HPLC to give the title compound (95 mg) as a pale-yellow oil.
[0726] LC-MS, m/z; 473 [M+H]+
Preparations of Examples 170 to 177
##STR00282##
[0727] Wherein HX is hydrochloric acid or trifluoroacetic acid.
[0728] The compounds in the following table (i.e. Examples 170 to
177) were prepared in the same manner as in Example 168 except that
the
3-ethyl-1-(5-{1-[2-(piperidin-4-yl)ethyl]piperidin-4-yl}-1,2,4-oxadiazol--
3-yl)-1H-indazole bis(trifluoroacetate) and methyl chloroformate
were replaced with the corresponding starting compound and acid
chloride (defined as R--Cl), respectively. In order to obtain each
of the trifluoroacetates in the following table, the residue was
isolated/purified by reverse phase HPLC. Each free form of the
compounds in the following table was obtained by omitting the
conversion step into hydrochloride in Example 168.
TABLE-US-00030 TABLE 30 .sup.1H-NMR/ Ex. R.sup.3 R.sup.6 R.sup.7 R
Compound Name LC-MS, m/z 170 Et H H --Ms 3-ethyl-1- LC-MS, m/z;
[5-(1-{[1- 473 [M + H] + (methylsulfon- yl)piperidin-4-
yl]methyl}piper- idin-4-yl)-1,2,4- oxadiazol-3-yl]- 1H-indazole
trifluoroacetate 171 Et F H --CO.sub.2Me methyl 4-({4-[3-
.sup.1H-NMR (3-ethyl-6- (CDCl.sub.3) fluoro-1H- .delta.: 1.01-1.16
indazol-1-yl)- (2H, m), 1.44 1,2,4-oxadiazol- (3H, t, J = 7.6
5-yl]piperidin-1- Hz), 1.58-1.83 yl}methyl)piper- (3H, m), 1.98-
idine-1- 2.24 (8H, m), carboxylate 2.68-3.13 (7H, m), 3.69 (3H, s),
3.99-4.30 (2H, m), 7.08 (1H, td, J = 8.9, 2.2 Hz), 7.70 (1H, dd, J
= 8.8, 5.1 Hz), 7.98 (1H, dd, J = 9.3, 2.2 Hz). LC-MS, m/z; 471 [M
+ H] + 172 Et H F --CO.sub.2Me methyl 4-({4-[3- .sup.1H-NMR
(3-ethyl-7- (CDCl.sub.3) fluoro-1H- .delta.: 1.00-1.15
indazol-1-yl)- (2H, m), 1.44 1,2,4-oxadiazol- (3H, t, J = 7.6
5-yl]piperidin-1- Hz), 1.59-1.81 yl}methyl)piper- (3H, m), 1.96-
idine-1- 2.24 (8H, m), carboxylate 2.68-2.82 (2H, m), 2.86-3.13 (5H
m), 3.69 (3H, s), 4.00- 4.27 (2H, m), 7.20-7.30 (2H, m), 7.50-7.57
(1H, m). LC-MS, m/z; 471 [M + H] + 173 .sup.iPr H F --CO.sub.2Me
methyl 4-[(4-{3- .sup.1H-NMR [7-fluoro-3- (CD.sub.3OD)
(propan-2-yl)-1H- .delta.: 1.16-1.29(3H, indazol-1-yl]- m), 1.48
(6H, d, 1,2,4-oxadiazol- J = 7.0Hz), 1.25- 5-yl}piperidin-1- 3.25
(8H, m), yl)methyl]piper- 3.34-4.22 (10H, idine-1- m), 3.68 (3H,
carboxylate s), 7.31-7.36 hydrochloride (2H, m), 7.72- 7.75 (1H,
m). LC-MS, m/z; 485 [M + H] + 174 .sup.iPr H F ##STR00283##
1-{4-[(4-{3-[7- fluoro-3- (propan- 2-yl)-1H- indazol- 1-yl]-1,2,4-
oxadiazol-5- yl}piperidin-1- yl)methyl] piperidin-1- yl}propan-1-
one .sup.1H-NMR (CDCl.sub.3) .delta.: 1.06-1.10 (3H, m), 1.15 (3H,
t, J = 7.4 Hz), 1.50 (6H, d, J = 7.0Hz), 1.7-1.9(3H, m), 2.0-2.30
(7H, m), 2.25-2.40 (2H, m), 2.50- 2.65(1H, m), 2.80-3.10(4H, m),
3.40-3.50 (1H, m), 3.80- 3.98 (1H, m), 4.50-4.70(1H, m), 7.14-7.30
(2H, m), 7.58- 7.61 (1H, m). LC-MS, m/z; 483 [M + H] + 175 Et H F
--Ms 3-ethyl-7-fluoro- 1-[5-(1-{[1- (methylsulfon- yl)piperidin-4-
yl]methyl}piper- idin-4-yl)-1,2,4- oxadiazol-3-yl]- 1H-indazole
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.06-1.16 (2H, m), 1.34 (3H, t,
J = 7.6 Hz), 1.58-1.66 (1H, m), 1.75- 1.86 (4H, m), 2.04-2.13 (4H,
m), 2.17 (2H, d, J = 7.3 Hz), 2.63-2.71 (2H, m), 2.82-2.86 (2H, m),
2.82 (3H, s), 3.03 (2H, q, J = 7.6 Hz), 3.10-3.18 (1H, m), 3.53
(2H, d, J = 11.7 Hz), 7.34-7.40 (1H, m), 7.42- 7.48 (1H, m), 7.77
(1H, d, J = 7.3 Hz). LC-MS, m/z; 491 [M + H] + 176 Et H F
##STR00284## 4-({4-[3-(3- ethyl-7-fluoro- 1H-indazol-1-yl)-
1,2,4-oxadiazol- 5-yl]piperidin-1- yl}methyl)-N,N- dimethyl-
piperidine- 1-carboxamide .sup.1H-NMR (DMSO-d.sub.6) .delta.:
0.97-1.06 (2H, m), 1.34 (3H, t, J = 7.6 Hz), 1.67 (3H, d, J = 10.5
Hz), 1.75-1.85 (2H, m), 2.04-2.16 (6H, m), 2.63- 2.70 (8H, m),
2.80-2.85 (2H, m), 3.03 (2H, q, J = 7.6 Hz), 3.10-3.20 (1H, m),
3.51 (2H, d, J = 12.4 Hz), 7.34-7.40 (1H, m), 7.41-7.48 (1H, m),
7.77 (1H, d, J = 7.3 Hz). LC-MS, m/z; 484 [M + H] + 177 Et H F
--CO.sub.2Et ethyl 4-({4-[3- (3-ethyl-7- fluoro-1H- indazol-1-yl)-
1,2,4-oxadiazol- 5-yl]piperidin-1- yl}methyl)piper- idine-1-
carboxylate .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.94 (2H, q, J =
11.5 Hz), 1.15 (3H, t, J = 7.1 Hz), 1.34 (3H, t, J = 7.6 Hz),
1.65-1.85 (5H, m), 2.05- 2.14 (6H, m), 2.73 (4H, d, J = 60.7 Hz),
3.03 (2H, q, J = 7.6 Hz), 3.09-3.18 (1H, m), 3.92- 4.03 (4H, m),
7.34-7.39 (1H, m), 7.37 (1H, td, J = 7.8, 4.1 Hz), 7.77 (1H, d, J =
7.8 Hz). LC-MS, m/z; 485 [M + H] +
Preparations of Examples 178 to 185
##STR00285##
[0729] Wherein HX is hydrochloric acid or trifluoroacetic acid.
[0730] The compounds in the following table (i.e. Examples 178 to
185) were prepared in the same manner as in Example 168 except that
the
3-ethyl-1-(5-{1-[2-(piperidin-4-yl)ethyl]piperidin-4-yl}-1,2,4-oxadiazol--
3-yl)-1H-indazole bis(trifluoroacetate) and methyl chloroformate
were replaced with the corresponding starting compound and acid
chloride (defined as R--Cl) or acetic anhydride, respectively. Each
free form of the compounds in the following table was obtained by
omitting the conversion step into hydrochloride in Example 168.
TABLE-US-00031 TABLE 31 .sup.1H-NMR/ Ex. R.sup.3 R.sup.6 R.sup.7 R
Compound Name LC-MS, m/z 178 Et H H --CO.sub.2Me methyl (2S)-2-
({4-[3-(3-ethyl- 1H-indazol-1-yl)- 1,2,4-oxadiazol-
5-yl]piperidin-1- yl}methyl)pyrrolidine- 1-carboxylate LC-MS, m/z;
439 [M + H]+ 179 Me F H --CO.sub.2Me methyl (2S)-2-
({4-[3-(6-fluoro- 3-methyl-1H- indazol-1-yl)- 1,2,4-oxadiazol-
5-yl]piperidin-1- yl}methyl)pyrrolidine- 1-carboxylate
hydrochloride LC-MS, m/z; 443 [M + H]+ 180 Et F H --CO.sub.2Me
methyl (2S)-2- ({4-[3-(3-ethyl- 6-fluoro-1H- indazol-1-yl)-
1,2,4-oxadiazol- 5-yl]piperidin-1- yl}methyl)pyrrolidine-
1-carboxylate LC-MS, m/z; 457 [M + H]+ 181 Et H F --Ac
1-[(2S)-2-({4-[3- (3-ethyl-7- fluoro-1H- indazol-1-yl)-
1,2,4-oxadiazol- 5-yl]piperidin-1- yl}methyl)pyrrolidin-
1-yl]ethanone LC-MS, m/z; 441 [M + H]+ 182 Et H F ##STR00286##
2-fluoroethyl (2S)-2-({4-[3-(3- ethyl-7-fluoro- 1H-indazol-1-yl)-
1,2,4-oxadiazol- 5-yl]piperidin-1- yl}methyl)pyrrolidine-
1-carboxylate .sup.1H-NMR (DMSO- d.sub.6) .delta.: 1.34 (3H, t, J =
7.6 Hz), 1.72-1.91 (6H, m), 2.01-2.17 (3H, m), 2.18-2.31 (2H, m),
2.41 (1H, t, J = 13.0 Hz), 2.81 (1H, d, J = 10.8 Hz), 2.96 (1H, d,
J = 10.8 Hz), 3.02 (2H, q, J = 7.8 Hz), 3.13 (1H, m), 3.21-3.31
(2H, brm), 3.87 (1H, s), 4.20 (2H, d, J = 29.5 Hz), 4.58 (2H, d, J
= 47.8 Hz), 7.36 (1H, m), 7.44 (1H, m), 7.76 (1H, d, J = 8.0 Hz).
LC-MS, m/z; 489 [M + H]+ 183 Et H F --CO.sub.2Me methyl (2S)-2-
({4-[3-(3-ethyl- 7-fluoro-1H- indazol-1-yl)- 1,2,4-oxadiazol-
5-yl]piperidin-1- yl}methyl)pyrrolidine- 1-carboxylate .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.44 (3H, t, J = 7.6 Hz), 1.80-2.40 (12H, m),
2.88 (1H, d, J = 10.6 Hz), 2.95-3.22 (4H, m), 3.26-3.46 (2H, m),
3.69 (3H, s), 3.97 (1H, m), 7.19-7.32 (2H, m), 7.53 (1H, m). LC-MS,
m/z; 457 [M + H]+ 184 .sup.iPr H F --CO.sub.2Me methyl (2S)-2-
[(4-{3-[7-fluoro- 3-(propan-2-yl)- 1H-indazol-1-yl]-
1,2,4-oxadiazol- 5-yl}piperidin-1- yl)methyl]pyrrolidine-
1-carboxylate .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (6H, d, J =
7.0), 1.45- 1.55 (3H, m), 1.80-3.10 (12H, m), 3.28-3.43 (2H, m),
3.46-3.51 (1H, m), 3.70 (3H, s), 3.91-4.03 (1H, m), 7.18-7.32 (2H,
m), 7.57-7.61 (1H, m). LC-MS, m/z; 471 [M + H]+ 185 Et H F --Ms
3-ethyl-7-fluoro- 1-[5-(1-{[(2S)-1- (methylsulfonyl) pyrrolidin-2-
yl]methyl}piperidin- 4-yl)-1,2,4- oxadiazol-3-yl]- 1H-indazole
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (3H, t, J = 7.6 Hz),
1.88-2.38 (11H, m), 2.59 (1H, m), 2.93 (3H, s), 2.96-3.14 (5H, m),
3.33-3.43 (2H, m), 3.91 (1H, m), 7.19-7.31 (2H, m), 7.53 (1H, m).
LC-MS, m/z; 477 [M + H]+
Preparations of Examples 186 to 190
##STR00287##
[0731] Wherein HX is hydrochloric acid or trifluoroacetic acid.
[0732] The compounds in the following table (i.e. Examples 186 to
190) were prepared in the same manner as in Example 168 except that
the
3-ethyl-1-(5-{1-[2-(piperidin-4-yl)ethyl]piperidin-4-yl}-1,2,4-oxadiazol--
3-yl)-1H-indazole bis(trifluoroacetate) and methyl chloroformate
were replaced with the corresponding starting compound and acid
chloride (defined as R--Cl) or acetic anhydride, respectively. Each
free form of the compounds in the following table was obtained by
omitting the conversion step into hydrochloride in Example 168.
TABLE-US-00032 TABLE 32 Ex. R.sup.3 R.sup.6 R.sup.7 R Compound Name
.sup.1H-NMR/LC-MS, m/z 186 Et H H --CO.sub.2Me methyl (2R)-2-
({4-[3-(3-ethyl- 1H-indazol-1-yl)- 1,2,4-oxadiazol-
5-yl]piperidin-1- yl}methyl)pyrrolidine- 1-carboxylate .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 1.35 (3H, t, J = 7.6 Hz), 1.75-1.90 (6H,
m), 2.05-2.19 (3H, m), 2.20-2.35 (2H, m), 2.80-2.85 (1H, m),
2.93-3.06 (3H, m), 3.08-3.16 (1H, m), 3.21-3.30 (2H, m), 3.44-3.50
(1H, m), 3.56 (3H, s), 3.87 (1H, s), 7.38 (1H, m), 7.64- 7.64 (1H,
m), 7.94 (1H, d, J = 8.1 Hz), 8.20 (1H, d, J = 8.5 Hz). LC-MS, m/z;
439 [M + H]+ 187 Et H F --Ac 1-[(2R)-2-({4-[3- (3-ethyl-7-
fluoro-1H- indazol-1-yl)- 1,2,4-oxadiazol- 5-yl]piperidin-1-
yl}methyl)pyrrolidin- 1-yl]ethanone .sup.1H-NMR (CDCl.sub.3)
.delta.: 1.44 (3H, t, J = 7.6 Hz), 1.95-2.59 (13H, m), 2.85-3.24
(6H, m), 3.34-3.75 (4H, m), 7.20-7.31 (2H, m), 7.54 (1H, m). LC-MS,
m/z; 441 [M + H]+ 188 Et H F --CO.sub.2Me methyl (2R)-2-
({4-[3-(3-ethyl- 7-fluoro-1H- indazol-1-yl)- 1,2,4-oxadiazol-
5-yl]piperidin-1- yl}methyl)pyrrolidine- 1-carboxylate
hydrochloride LC-MS, m/z; 457 [M + H]+ 189 Et H F ##STR00288##
l-[(2R)-2-({4-[3- (3-ethyl-7- fluoro-1H- indazol-1-yl)-
1,2,4-oxadiazol- 5-yl]piperidin-1- yl}methyl)pyrrolidin- 1-yl]-2-
methoxyethanone LC-MS, m/z; 471 [M + H]+ 190 Et H F --Ms
3-ethyl-7-fluoro- 1-[5-(1-{[(2R)-1- (methylsulfonyl) pyrrolidin-2-
yl]methyl}piperidin- 4-yl)-1,2,4- oxadiazol-3-yl]- 1H-indazole
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (3H, t, J = 7.6 Hz), 1.
88-2.38 (11H, m), 2.59 (1H, m), 2.93 (3H, s), 2.96-3.14 (5H, m),
3.33-3.43 (2H, m), 3.91 (1H, m), 7.19- 7.31 (2H, m), 7.53 (1H, m).
LC-MS, m/z; 477 [M + H]+
Preparations of Examples 191 to 203
##STR00289##
[0733] Wherein HX is hydrochloric acid or trifluoroacetic acid.
[0734] The compounds in the following table (i.e. Examples 191 to
203) were prepared in the same manner as in Example 168 except that
the
3-ethyl-1-(5-{1-[2-(piperidin-4-yl)ethyl]piperidin-4-yl}-1,2,4-oxadiazol--
3-yl)-1H-indazole bis(trifluoroacetate) and methyl chloroformate
were replaced with the corresponding starting compound and acid
chloride (defined as R--Cl) or acetic anhydride, respectively. Each
free form of the compounds in the following table was obtained by
omitting the conversion step into hydrochloride in Example 168.
TABLE-US-00033 TABLE 33 .sup.1H-NMR/ Ex. R.sup.3 R.sup.6 R.sup.7 R
Compound Name LC-MS, m/z 191 Et H H --Ac 1-[(3S)-3-({4-[3-(3-
ethyl-1H-indazol-1- yl)-1,2,4-oxadiazol- 5-yl]piperidin-1-
yl}methyl)pyrrolidin- 1-yl]ethanone LC-MS, m/z; 423 [M + H]+ 192 Et
H F --CO.sub.2Me methyl (3S)-3-({4-[3- (3-ethyl-7-fluoro-1H-
indazol-1-yl)-1,2,4- oxadiazol-5- yl]piperidin-1-
yl}methyl)pyrrolidine- 1-carboxylate .sup.1H-NMR (CDCl.sub.3)
.delta.: 1.44 (3H, t, J = 7.7 Hz), 1.55-1.80 (1H, m), 1.93-2.24
(7H, m), 2.28-2.51 (3H, m), 2.87-3.17 (6H, m), 3.27-3.65 (3H, m),
3.70 (3H, s), 7.20-7.32 (2H, m), 7.50-7.58 (1H, m). LC-MS, m/z; 457
[M + H]+ 193 Et F H --Ac 1-[(3S)-3-({4-[3-(3- ethyl-6-fluoro-1H-
indazol-1-yl)-1,2,4- oxadiazol-5- yl]piperidin-1-
yl}methyl)pyrrolidin- 1-yl]ethanone hydrochloride .sup.1H-NMR
(DMSO- d.sub.6) .delta.: 1.36 (3H, t, J = 7.6 Hz), 1.57-1.85 (1H,
m), 1.88-2.00 (3H, m), 2.02-2.24 (1H, m), 2.26-2.55 (4H, m),
2.58-2.84 (1H, m), 2.92-3.25 (7H, m), 3.27-3.82 (6H, m), 7.26-7.36
(1H, m), 7.86-7.97 (1H, m), 7.99-8.07 (1H, m), 10.62-11.10 (1H, m).
LC-MS, m/z; 441 [M + H]+ 194 Et F H --CO.sub.2Me methyl
(3S)-3-({4-[3- (3-ethyl-6-fluoro-1H- indazol-1-yl)-1,2,4-
oxadiazol-5- yl]piperidin-1- yl}methyl)pyrrolidine- 1-carboxylate
hydrochloride .sup.1H-NMR (DMSO- d.sub.6) .delta.: 1.36 (3H, t, J =
7.6 Hz), 1.60-1.81 (1H, m), 2.01-2.21 (1H, m), 2.26-2.54 (4H, m),
2.59-2.80 (1H, m), 2.96-3.31 (8H, m), 3.35-3.77 (8H, m), 7.26-7.36
(1H, m), 7.87-8.10 (2H, m), 10.60-10.88 (1H, m). LC-MS, m/z; 457 [M
+ H]+ 195 Et H H ##STR00290## 2-fluoroethyl (3S)-3-
({4-[3-(3-ethyl-1H- indazol-1-yl)-1,2,4- oxadiazol-5-
yl]piperidin-1- yl}methyl)pyrrolidine- 1-carboxylate LC-MS, m/z;
471 [M + H]+ 196 .sup.iPr H F --Ac l-{(3S)-3-[(4-{3-[7-
fluoro-3-(propan-2- yl)-1H-indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}piperidin-1- yl)methyl]pyrrolidin- 1-yl}ethanone hydrochloride
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (6H, d, J = 7.0 Hz),
2.0-2.60 (13H, m), 2.90-3.75 (9H, m), 7.20-7.28 (2H, m), 7.58-7.61
(1H, m). LC-MS, m/z; 455 [M + H]+ 197 .sup.iPr H F --CO.sub.2Me
methyl (3S)-3-[(4-{3- [7-fluoro-3-(propan- 2-yl)-1H-indazol-1-
yl]-1,2,4-oxadiazol- 5-yl}piperidin-1- yl)methyl]pyrrolidine-
1-carboxylate hydrochloride .sup.1H-NMR (CD.sub.3OD) .delta.: 1.47
(6H, d, J = 7.0 Hz), 2.15-3.10 (8H, m), 3.29-3.81 (11H, m), 3.69
(3H, s), 7.30-7.36 (2H, m), 7.71-7.74 (1H, m). LC-MS, m/z; 471 [M +
H]+ 198 .sup.iPr H F ##STR00291## 1-{(3S)-3-[(4-{3-[7-
fluoro-3-(propan-2- yl)-1H-indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}piperidin-1- yl)methyl]pyrrolidin- 1-yl}propan-1-one
hydrochloride .sup.1H-NMR (CD.sub.3OD) .delta.: 1.09-1.15 (4H, m),
1.48 (6H, d, J = 7.0 Hz), 2.10- 2.70 (7H, m), 3.10-3.35 (5H, m),
3.47-3.54 (3H, m), 3.60-3.75 (2H, m), 3.78- 3.90 (3H, m), 7.30-7.36
(2H, m), 7.70-7.77 (1H, m). LC-MS, m/z; 469 [M + H]+ 199 .sup.iPr H
F ##STR00292## cyclopropyl{(3S)-3- [(4-{3-[7-fluoro-3-
(propan-2-yl)-1H- indazol-1-yl]-1,2,4- oxadiazol-5- yl}piperidin-1-
yl)methyl]pyrrolidin- 1-yl}methanone hydrochloride .sup.1H-NMR
(CD.sub.3OD) .delta.: 0.80-0.90 (4H, m), 1.47 (6H, d, J = 7.0 Hz),
1.80-2.58 (9H, m), 3.26-3.85 (11H, m), 7.30-7.36 (2H, m), 7.71-7.74
(1H, m). LC-MS, m/z; 481 [M + H]+ 200 .sup.iPr H F ##STR00293##
1-{(3S)-3-[(4-{3-[7- fluoro-3-(propan-2- yl)-1H-indazol-1-yl]-
1,2,4-oxadiazol-5- yl}piperidin-1- yl)methyl]pyrrolidin- 1-yl}-2-
methoxyethanone .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30-1.48 (4H,
m), 1.50 (6H, d, J = 6.8 Hz), 1.93-2.55 (6H, m), 3.20-4.00 (11H,
m), 4.06 (3H, s), 7.25-7.31 (2H, m), 7.61-7.63 (1H, m). LC-MS, m/z;
485 [M + H]+ 201 Et H F --Ac 1-[(3S)-3-({4-[3-(3-
ethyl-7-fluoro-1H- indazol-1-yl)-1,2,4- oxadiazol-5-
yl]piperidin-1- yl}methyl)pyrrolidin- 1-yl]ethanone .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.44 (3H, t, J = 7.6 Hz), 1.95-2.59 (13H, m),
2.85-3.24 (6H, m), 3.34-3.75 (4H, m), 7.20-7.31 (2H, m), 7.54 (1H,
m). LC-MS, m/z; 441 [M + H]+ 202 Et H F ##STR00294##
1-[(3S)-3-({4-[3-(3- ethyl-7-fluoro-1H- indazol-1-yl)-1,2,4-
oxadiazol-5- yl]piperidin-1- yl}methyl)pyrrolidin- 1-yl]-2-
methoxyethanone .sup.1H-NMR (CDCl3) .delta.: 1.36-1.83 (4H, m),
1.92-2.61 (10H, m), 2.85-3.81 (12H, m), 4.04 (2H, d, J = 3.5 Hz),
7.19-7.34 (2H, m), 7.50-7.59 (1H, m). LC-MS, m/z; 471 [M + H]+. 203
Et H F --Ms 3-ethyl-7-fluoro-1- [5-(1-{[(3S)-1- (methylsulfonyl)
pyrrolidin-3- yl]methyl}piperidin- 4-yl)-1,2,4- oxadiazol-3-yl]-1H-
indazole .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (3H, t, J = 7.6
Hz), 1.71 (1H, m), 1.96-2.58 (10H, m), 2.84 (3H, s), 2.86-3.15 (6H,
m) 3.27- 3.56 (3H, m), 7.20-7.31 (2H, m), 7.54 (1H, m). LC-MS, m/z;
477 [M + H]+
Preparations of Examples 204 to 216
##STR00295##
[0735] Wherein HX is hydrochloric acid or trifluoroacetic acid.
[0736] The compounds in the following table (i.e. Examples 204 to
216) were prepared in the same manner as in Example 168 except that
the
3-ethyl-1-(5-{1-[2-(piperidin-4-yl)ethyl]piperidin-4-yl}-1,2,4-oxadiazol--
3-yl)-1H-indazole bis(trifluoroacetate) and methyl chloroformate
were replaced with the corresponding starting compound and acid
chloride (defined as R--Cl) or acetic anhydride, respectively. Each
free form of the compounds in the following table was obtained by
omitting the conversion step into hydrochloride in Example 168.
TABLE-US-00034 TABLE 34 .sup.1H-NMR/ Ex. R.sup.3 R.sup.6 R.sup.7 R
Compound Name LC-MS, m/z 204 Et H F --CO.sub.2Me methyl (3R)-3-({4-
[3-(3-ethyl-7- fluoro-1H-indazol- 1-yl)-1,2,4- oxadiazol-5-
yl]piperidin-1- yl}methyl)pyrrolidine- 1-carboxylate .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.44 (3H, t, J = 7.7 Hz), 1.54-1.73 (1H, m),
1.92-2.25 (7H, m), 2.27-2.50 (3H, m), 2.87-3.17 (6H, m), 3.27-3.66
(3H, m), 3.70 (3H, s), 7.20-7.32 (2H, m), 7.50-7.58 (1H, m). LC-MS,
m/z; 457 [M + H]+ 205 Et F H --Ac 1-[(3R)-3-({4-[3-
(3-ethyl-6-fluoro- 1H-indazol-1-yl)- 1,2,4-oxadiazol-5-
yl]piperidin-1- yl}methyl)pyrrolidin- 1-yl]ethanone hydrochloride
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.36 (3H, t, J = 7.6 Hz), 1.57-
1.84 (1H, m), 1.87-1.99 (3H, m), 2.02-2.54 (5H, m), 2.58- 2.86 (1H,
m), 2.91-3.26 (7H, m), 3.27-3.82 (6H, m), 7.23- 7.37 (1H, m),
7.83-8.10 (2H, m), 10.58-11.07 (1H, m). LC-MS, m/z; 441 [M + H]+
206 Et F H --CO.sub.2Me methyl (3R)-3-({4- [3-(3-ethyl-6-
fluoro-1H-indazol- 1-yl)-1,2,4- oxadiazol-5- yl]piperidin-1-
yl}methyl)pyrrolidine- 1-carboxylate hydrochloride .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 1.36 (3H, t, J = 7.6 Hz), 1.59- 1.82 (1H,
m), 2.04-2.19 (1H, m), 2.26-2.48 (4H, m), 2.61- 2.82 (1H, m),
2.98-3.29 (8H, m,) 3.33-3.81 (8H, m), 7.26- 7.36 (1H, m), 7.86-8.11
(2H, m), 10.57-10.88 (1H, m). LC-MS, m/z; 457 [M + H]+ 207 Et H H
##STR00296## 2-fluoroethyl (3R)-3-({4-[3-(3- ethyl-1H-indazol-
1-yl)-1,2,4- oxadiazol-5- yl]piperidin-1- yl}methyl)pyrrolidine-
1-carboxylate LC-MS, m/z; 471 [M + H]+ 208 Et H H --Ac
1-[(3R)-3-({4-[3- (3-ethyl-1H- indazol-1-yl)- 1,2,4-oxadiazol-5-
yl]piperidin-1- yl}methyl)pyrrolidin- 1-yl]ethanone LC-MS, m/z; 423
[M + H]+ 209 Et H F --Ac 1-[(3R)-3-({4-[3- (3-ethyl-7-fluoro-
1H-indazol-1-yl)- 1,2,4-oxadiazol-5- yl]piperidin-1-
yl}methyl)pyrrolidin- 1-yl]ethanone hydrochloride .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 1.36 (3H, t, J = 7.5 Hz), 1.57- 1.87 (1H,
m), 1.89-2.01 (3H, m), 2.02-2.55 (5H, m), 2.58- 2.88 (1H, m),
2.91-3.27 (7H, m), 3.28-3.83 (6H, m), 7.34- 7.54 (2H, m), 7.76-7.84
(1H, m), 10.71-11.26 (1H, br m). LC-MS, m/z; 441 [M + H]+ 210 Et H
F ##STR00297## 1-[(3R)-3-({4-[3- (3-ethyl-7-fluoro-
1H-indazol-1-yl)- 1,2,4-oxadiazol-5- yl]piperidin-1-
yl}methyl)pyrrolidin- 1-yl]-2- methoxyethanone hydrochloride
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.32-1.52 (3H, m), 1.67-4.29
(25H, m), 7.18-7.34 (2H, m), 7.47-7.61 (1H, m), 11.82-12.56 (1H, br
m). LC-MS, m/z; 471 [M + H]+ 211 .sup.iPr H F --Ac
1-{(3R)-3-[(4-{3- [7-fluoro-3- (propan-2-yl)-1H- indazol-1-yl]-
1,2,4-oxadiazol-5- yl}piperidin-1- yl)methyl]pyrrolidin-
1-yl}ethanone hydrochloride .sup.1H-NMR (CD.sub.3OD) .delta.: 1.47
(6H, d, J = 7.0 Hz), 1.83-2.93 (12H, m), 3.35-4.72 (10H, m),
7.30-7.35 (2H, m), 7.72-7.75 (1H, m). LC-MS, m/z; 455 [M + H]+ 212
.sup.iPr H F --CO.sub.2Me methyl (3R)-3-[(4- {3-[7-fluoro-3-
(propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5- yl}piperidin-1-
yl)methyl]pyrrolidine- 1-carboxylate hydrochloride .sup.1H-NMR
(CD.sub.3OD) .delta.: 1.46 (6H, d, J = 7.0 Hz), 2.15-2.86 (6H, m),
3.09-3.80 (13H, m), 3.68 (3H, s), 7.29-7.35 (2H, m), 7.70-7.73 (1H,
m). LC-MS, m/z; 471 [M + H]+ 213 .sup.iPr H F ##STR00298##
1-{(3R)-3-[(4-{3- [7-fluoro-3- (propan-2-yl)-1H- indazol-1-yl]-
1,2,4-oxadiazol-5- yl}piperidin-1- yl)methyl]pyrrolidin-
1-yl}propan-1- one .sup.1H-NMR (CDCl.sub.3) .delta.: 1.16 (3H, t, J
= 7.4 Hz), 1.50 (6H, d, J = 7.0 Hz), 2.05-2.36 (12H, m), 2.92-3.20
(4H, m), 3.38-3.70 (5H, m), 7.20- 7.25 (2H, m), 7.57-7.61 (1H, m).
LC-MS, m/z; 469 [M + H]+ 214 .sup.iPr H F ##STR00299##
cyclopropyl{(3R)- 3-[(4-{3-[7- fluoro-3-(propan- 2-yl)-1H-indazol-
1-yl]-1,2,4- oxadiazol-5- yl}piperidin-1- yl)methyl]pyrrolidin-
1-yl}methanone .sup.1H-NMR (CDCl.sub.3) .delta.: 0.74-0.78 (2H, m),
0.94-1.07 (2H, m), 1.50 (6H, d, J = 7.0 Hz), 2.02-2.22 (8H, m),
2.38-3.41 (2H, m), 2.87-3.19 (4H, m), 3.36-3.62 (6H, m), 7.20-7.25
(2H, m), 7.58-7.61 (1H, m). LC-MS, m/z; 481 [M + H]+ 215 .sup.iPr H
F ##STR00300## 1-{(3R)-3-[(4-{3- [7-fluoro-3- (propan-2-yl)-1H-
indazol-1-yl]- 1,2,4-oxadiazol-5- yl}piperidin-1-
yl)methyl]pyrrolidin- 1-yl}-2- methoxyethanone .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.50 (6H, d, J = 7.0 Hz), 2.05-2.55 (9H, m),
2.92-3.22 (5H, m), 3.42- 3.79 (8H, m), 4.04-4.06 (2H, m), 7.20-7.25
(2H, m), 7.58-7.60 (1H, m). LC-MS, m/z; 485 [M + H]+ 216 Et H F
--Ms 3-ethyl-7-fluoro- 1-[5-(1-{[(3R)-1- (methylsulfonyl)
pyrrolidin-3- yl]methyl}piperidin- 4-yl)-1,2,4- oxadiazol-3-yl]-
1H-indazole .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (3H, t, J = 7.6
Hz), 1.71 (1H, m), 1.96-2.58 (10H, m), 2.84 (3H, s), 2.86-3.15 (6H,
m) 3.27-3.56 (3H, m), 7.20-7.31 (2H, m), 7.54 (1H, m). LC-MS, m/z;
477 [M + H]+
Preparations of Examples 217 to 226
##STR00301##
[0737] Wherein HX is hydrochloric acid or trifluoroacetic acid.
[0738] The compounds in the following table (i.e. Examples 217 to
226) were prepared in the same manner as in Example 168 except that
the
3-ethyl-1-(5-{1-[2-(piperidin-4-yl)ethyl]piperidin-4-yl}-1,2,4-oxadiazol--
3-yl)-1H-indazole bis(trifluoroacetate) and methyl chloroformate
were replaced with the corresponding starting compound and acid
chloride (defined as R--Cl) or acetic anhydride, respectively. Each
free form of the compounds in the following table was obtained by
omitting the conversion step into hydrochloride in Example 168.
TABLE-US-00035 TABLE 35 Ex. R.sup.3 R.sup.6 R.sup.7 R Compound Name
.sup.1H-NM/LC-MS, m/z 217 Et F H --CO.sub.2Me methyl 3-({4-
[3-(3-ethyl-6- fluoro-1H- indazol-1-yl)- 1,2,4- oxadiazol-5-
yl]piperidin- 1-yl}methyl) azetidine-1- carboxylate .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.44 (3H, t, J = 7.6 Hz), 1.95-2.28 (6H, m),
2.54-2.69 (2H, m), 2.71-3.15 (6H, m), 3.60-3.74 (5H, m), 4.09 (2H,
t, J = 8.4 Hz), 7.08 (1H, td, J = 8.8, 2.2 Hz), 7.70 (1H, dd, J =
8.7, 5.0 Hz), 7.97 (1H, dd, J = 9.4, 1.7 Hz). LC-MS, m/z; 443 [M +
H]+ 218 Et H F --CO.sub.2Me methyl 3-({4- [3-(3-ethyl-7- fluoro-1H-
indazol-1-yl)- 1,2,4- oxadiazol-5- yl]piperidin- 1-yl}methyl)
azetidine-1- carboxylate .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44
(3H, t, J = 7.6 Hz), 1.96-2.26 (6H, m), 2.61 (2H, d, J = 7.6 Hz),
2.72-2.94 (3H, m), 2.98-3.13 (3H, m), 3.62-3.74 (5H, m), 4.08 (2H,
t, J = 8.3 Hz), 7.20-7.30 (2H, m), 7.50-7.56 (1H, m). 219 .sup.iPr
H F --Ac 1-{3-[(4-{3- [7-fluoro-3- (propan-2-yl)- 1H-indazol-1-
yl]-1,2,4- oxadiazol-5- yl}piperidin- 1-yl)methyl] azetidin-1-
yl}ethanone hydrochloride .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.41
(6H, d, J = 7.1 Hz), 1.69-1.77 (3H, m), 2.18-2.42 (3H, m),
3.02-3.20 (3H, m), 3.31-3.59 (7H, m), 3.62-3.76 (1H, m), 3.89-4.03
(2H, m), 4.20-4.31 (1H, m), 7.33-7.52 (2H, m), 7.80-7.88 (1H, m),
10.89- 11.11 (1H, m). LC-MS, m/z; 441 [M + H]+ 220 .sup.iPr H F
--CO.sub.2Me methyl 3-[(4 {3-[7-fluoro- 3-(propan-2- yl)-1H-
indazol-1-yl]- 1,2,4- oxadiazol-5- yl}piperidin- 1-yl)methyl]
azetidine-1- carboxylate hydrochloride .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 1.41 (6H, d, J = 6.8 Hz), 2.13-2.41 (4H, m), 3.00-3.20
(3H, m), 3.30-3.59 (9H, m), 3.68-3.86 (2H, m), 3.94-4.13 (2H, m),
7.31-7.53 (2H, m), 7.78-7.89 (1H, m), 10.74- 10.98 (1H, m). LC-MS,
m/z; 457 [M + H]+ 221 .sup.iPr H F ##STR00302## 1-{3-[(4-{3-
[7-fluoro-3- (propan-2-yl)- 1H-indazol-1- yl]-1,2,4- oxadiazol-5-
yl}piperidin- 1-yl)methyl] azetidin-1-yl}-2- methoxyethanone
hydrochloride .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.41 (6H, d, J =
6.8 Hz), 2.17-2.45 (4H, m), 3.03-3.60 (12H, m), 3.69- 3.80 (1H, m),
3.85-4.12 (4H, m), 4.26-4.38 (1H, m), 7.35-7.54 (2H, m), 7.82-7.90
(1H, m), 10.86-11.11 (1H, m). LC-MS, m/z; 471 [M + H]+ 222 .sup.iPr
H F ##STR00303## cyclopropyl{3- [(4-{3-[7- fluoro-3- (propan-2-yl)-
1H-indazol-1- yl]-1,2,4- oxadiazol-5- yl}piperidin- 1-yl)methyl]
azetidin-1- yl}methanone hydrochloride .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 0.62-0.78 (4.0H, m), 1.36-1.54 (7H, m), 2.17-2.45 (4H, m),
3.04-3.25 (3H, m), 3.35-3.62 (6H, m), 3.64-3.78 (1H, m), 3.93-4.16
(2H, m), 4.34-4.47 (1H, m), 7.35-7.55 (2H, m), 7.81-7.90 (1H, m),
10.82-11.07 (1H, m). LC-MS, m/z; 467 [M + H]+ 223 Et H F --Ac
1-[3-({4-[3-(3- ethyl-7-fluoro- 1H-indazol-1- yl)-1,2,4-
oxadiazol-5- yl]piperidin-1- yl}methyl) azetidin-1- yl]ethanone
hydrochloride .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35 (3H, t, J =
7.5 Hz), 1.73 (3H, s), 2.10-2.21 (2H, m), 2.31-2.40 (3H, m),
3.00-3.10 (4H, m), 3.36-3.40 (3H, m), 3.51-3.55 (2H, m), 3.64-3.69
(1H, m), 3.91-4.00 (2H, m), 4.22-4.27 (1H, m), 7.37-7.41 (1H, m),
7.44-7.49 (1H, m), 7.78 (1H, d, J = 7.7 Hz). LC-MS, m/z; 427 [M +
H]+ 224 Et H F ##STR00304## 1-[3-({4-[3-(3- ethyl-7-fluoro-
1H-indazol-1- yl)-1,2,4- oxadiazol-5- yl]piperidin-1- yl}methyl)
azetidin-1-yl]-2- methoxyethanone hydrochloride .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.36 (3H, t, J = 7.6 Hz), 2.17-2.46 (4H, m),
3.00-3.24 (5H, m), 3.28 (3H, s), 3.36-3.59 (5H, m), 3.69-3.80 (1H,
m), 3.89 (2H, s), 3.95-4.10 (2H, m), 4.27-4.37 (1H, m), 7.36-7.52
(2H, m), 7.77-7.82 (1H, m), 10.85-11.16 (1H, br m). LC-MS, m/z; 457
[M + H]+ 225 Et H F ##STR00305## 1-[3-({4-[3-(3- ethyl-7-fluoro-
1H-indazol-1- yl)-1,2,4- oxadiazol-5- yl]piperidin-1- yl}methyl)
azetidin-1-yl]- 3,3,3- trifluoropropan- 1-one hydrochloride LC-MS,
m/z; 495 [M + H]+ 226 Et H F --Ms 3-ethyl-7- fluoro-1-[5-(1- {[1-
(methylsulfonyl) azetidin-3- yl]methyl} piperidin-4-yl)- 1,2,4-
oxadiazol-3- yl]-1H-indazole .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.34 (3H, t, J = 7.6 Hz), 1.79 (2H, q, J = 11.0 Hz), 2.05-2.17 (4H,
m), 2.54 (2H, d, J = 7.3 Hz), 2.77-2.84 (3H, m), 2.98-3.05 (5H, m),
3.14 (1H, m), 3.55 (2H, t, J = 7.1 Hz), 3.89 (2H, t, J = 8.0 Hz),
7.34-7.40 (1H, m), 7.42-7.48 (1H, m), 7.77 (1H, d, J = 8.0 Hz).
LC-MS, m/z; 463 [M + H]+
Preparations of Examples 227 to 241
##STR00306##
[0739] Wherein HX is hydrochloric acid or trifluoroacetic acid.
[0740] The compounds in the following table (i.e. Examples 227 to
241) were prepared in the same manner as in Example 168 except that
the
3-ethyl-1-(5-{1-[2-(piperidin-4-yl)ethyl]piperidin-4-yl}-1,2,4-oxadiazol--
3-yl)-1H-indazole bis(trifluoroacetate) and methyl chloroformate
were replaced with the corresponding starting compound and acid
chloride (defined as R--Cl) or acetic anhydride, respectively. Each
free form of the compounds in the following table was obtained by
omitting the conversion step into hydrochloride in Example 168.
TABLE-US-00036 TABLE 36 .sup.1H-NMR/LC-MS, Ex. R.sup.3 R.sup.6
R.sup.7 R Compound Name m/z 227 Et H H --CO.sub.2Me methyl 4-[3-(3-
ethyl-1H- indazol-1-yl)- 1,2,4-oxadiazol- 5-yl]-1,4'-
bipiperidine-1'- carboxylate LC-MS, m/z; 439 [M + H]+ 228 Et F H
--Ac 1-{4-[3-(3- ethyl-6-fluoro- 1H-indazol-1- yl)-1,2,4-
oxadiazol-5-yl]- 1,4'-bipiperidin-1'- yl}ethanone hydrochloride
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.36 (3H, t, J = 7.4 Hz),
1.44-1.77 (2H, m), 1.97-2.21 (5H, m), 2.27-2.59 (5H, m), 2.95-3.27
(5H, m), 3.39-3.63 (4H, m), 3.88-4.04 (1H, m), 4.44-4.60 (1H, m),
7.25-7.37 (1H, m), 7.85-8.10 (2H, m), 10.86-11.09 (1H, m). LC-MS,
m/z; 441 [M + H]+ 229 Et H F --Ac 1-{4-[3-(3- ethyl-7-fluoro-
1H-indazol-1- yl)-1,2,4- oxadiazol-5-yl]- 1,4'-bipiperidin-1'-
yl}ethanone hydrochloride .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.36
(3H, t, J = 7.6 Hz), 1.43-1.76 (2H, m), 1.96-2.20 (5H, m),
2.23-2.57 (5H, m), 2.94-3.27 (5H, m), 3.31-3.61 (4H, m), 3.89-4.04
(1H, m), 4.43-4.59 (1H, m), 7.34-7.53 (2H, m), 7.76-7.83 (1H, m),
10.81-11.00 (1H, m). LC-MS, m/z; 441 [M + H]+ 230 Et F H
--CO.sub.2Me methyl 4-[3-(3- ethyl-6-fluoro- 1H-indazol-1-
yl)-1,2,4- oxadiazol-5-yl]- 1,4'-bipiperidine-1'- carboxylate
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.38-1.57 (5H, m), 1.75- 1.87
(2H, m), 1.95-2.26 (4H, m), 2.33-2.58 (3H, m), 2.69- 2.87 (2H, m),
2.95-3.13 (5H, m), 3.70 (3H, s), 4.05-4.36 (2H, m), 7.08 (1H, td, J
= 8.8, 2.2 Hz), 7.70 (1H, dd, J = 8.7, 5.0 Hz), 7.98 (1H, dd, J =
9.5, 2.2 Hz). 231 Et H F --CO.sub.2Me methyl 4-[3-(3-
ethyl-7-fluoro- 1H-indazol-1- yl)-1,2,4- oxadiazol-5-yl]-
1,4'-bipiperidine-1'- carboxylate .sup.1H-NMR (CDCl.sub.3) .delta.:
1.36-1.54 (5H, m), 1.75-1.87 (2H, m), 1.94-2.24 (4H, m), 2.32-2.54
(3H, m), 2.69-2.85 (2H, m), 2.92-3.14 (5H, m), 3.69 (3H, s),
4.04-4.34 (2H, m), 7.19-7.30 (2H, m), 7.49- 7.57 (1H, m). 232
.sup.iPr H F --Ac 1-(4-{3-[7- fluoro-3- (propan-2-yl)-
1H-indazol-1- yl]-1,2,4- oxadiazol-5-yl}- 1,4'-bipiperidin-1'-
yl)ethanone hydrochloride .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.41
(6H, d, J = 6.8 Hz), 1.45-1.76 (2H, m), 1.96-2.21 (5H, m),
2.24-2.58 (5H, m), 2.96-3.27 (3H, m), 3.34-3.61 (5H, m), 3.89-4.04
(1H, m), 4.44-4.59 (1H, m), 7.34-7.53 (2H, m), 7.81-7.91 (1H, m),
10.86-11.12 (1H, m). LC-MS, m/z; 455 [M + H]+ 233 .sup.iPr H F
##STR00307## 1-(4-{3-[7- fluoro-3- (propan-2-yl)- 1H-indazol-1-
yl]-1,2,4- oxadiazol-5-yl}- 1,4'-bipiperidin-1'-yl)-
2-methoxyethanone hydrochloride .sup.1H-NMR (DMSO-d.sub.6) .delta.:
1.41 (6H, d, J = 6.8 Hz), 1.48-1.77 (2H, m), 2.07-2.66 (7H, m),
2.91-3.06 (1H, m), 3.10-3.63 (10H, m), 3.83-4.19 (3H, m), 4.41-4.57
(1H, m), 7.34-7.53 (2H, m), 7.80-7.90 (1H, m), 10.67-10.86 (1H, m).
LC-MS, m/z; 485 [M + H]+ 234 .sup.iPr H F --CO.sub.2Me methyl
4-{3-[7- fluoro-3- (propan-2-yl)- 1H-indazol-1- yl]-1,2,4-
oxadiazol-5-yl}- 1,4'-bipiperidine-1'- carboxylate hydrochloride
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.41 (6H, d, J = 6.8 Hz),
1.50-1.70 (2H, m), 2.05-2.19 (2H, m), 2.23-2.53 (4H, m), 2.68-2.93
(2H, m), 3.07-3.27 (2H, m), 3.39-3.63 (8H, m), 4.00-4.20 (2H, m),
7.33-7.52 (2H, m), 7.79-7.88 (1H, m), 10.95-11.12 (1H, m). LC-MS,
m/z; 471 [M + H]+ 235 .sup.iPr H F ##STR00308## 2-(dimethylamino)-
1-(4-{3-[7- fluoro-3-(propan-2-yl)- 1H-indazol-1-yl]-1,2,4-
oxadiazol-5-yl}- 1,4'-bipiperidin-1'- yl)ethanone LC-MS, m/z; 498
[M + H]+ 236 .sup.iPr H F ##STR00309## 4-{3-[7-fluoro-
3-(propan-2-yl)- 1H-indazol-1- yl]-1,2,4- oxadiazol-5-yl}-
N,N-dimethyl- 1,4'-bipiperidine-1'- carboxamide hydrochloride
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.41 (6H, d, J = 7.1 Hz),
1.54-1.75 (2H, m), 2.02-2.16 (2H, m), 2.23-2.48 (4H, m), 2.63-2.84
(8H, m), 3.09-3.27 (2H, m), 3.33-3.72 (7H, m), 7.33-7.54 (2H, m),
7.80-7.89 (1H, m), 10.80-10.95 (1H, m). LC-MS, m/z; 484 [M + H]+
237 Et H F ##STR00310## 1-{4-[3-(3- ethyl-7-fluoro- 1H-indazol-1-
yl)-1,2,4- oxadiazol-5-yl]- 1,4'-bipiperidin-1'-
yl}-2-methoxyethanone hydrochloride .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 1.36 (3H, t, J = 7.5 Hz), 1.43-1.77 (2H, m), 2.04-2.66
(7H, m), 2.91-3.65 (12H, m), 3.84-4.22 (3H, m), 4.41-4.56 (1H, m),
7.33-7.53 (2H, m), 7.76-7.84 (1H, m), 10.43 (1H, br s). LC-MS, m/z;
471 [M + H]+ 238 Et H F --CO.sub.2Et ethyl 4-[3-(3- ethyl-7-fluoro-
1H-indazol-1- yl)-1,2,4- oxadiazol-5-yl]- 1,4'-bipiperidine-1'-
carboxylate .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.16 (3H, t, J =
7.1 Hz), 1.34 (5H, t, J = 7.6 Hz), 1.69- 1.82 (4H, m), 2.08 (2H, d,
J = 11.0 Hz), 2.28-2.34 (2H, m), 2.67-2.90 (4H, m), 3.03 (2H, q, J
= 7.6 Hz), 3.06-3.17 (2H, m), 3.97-4.03 (4H, m), 7.34- 7.40 (1H,
m), 7.41-7.48 (1H, m), 7.77 (1H, d, J = 7.3 Hz). LC-MS, m/z; 471 [M
+ H]+ 239 Et F H ##STR00311## 1-{4-[3-(3- ethyl-6-fluoro-
1H-indazol-1- yl)-1,2,4- oxadiazol-5-yl]- 1,4'-bipiperidin-1'-
yl}-2-methoxyethanone .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.22-1.43
(5H, m), 1.72- 1.84 (4H, m), 2.10 (2H, d, J = 10.7 Hz), 2.34 (2H,
t, J = 10.5 Hz), 2.55 (2H, d, J = 12.4 Hz), 2.87-3.05 (5H, m),
3.09-3.15 (1H, m), 3.26 (3H, s), 3.78 (1H, d, J = 13.9 Hz), 4.05
(2H, dd, J = 29.4, 14.0 Hz), 4.35 (1H, d, J = 12.2 Hz), 7.25-7.31
(1H, m), 7.88-7.92 (1H, m), 7.98-8.03 (1H, m). LC-MS, m/z; 471 [M +
H]+ 240 Et H Cl --Ac 1-{4-[3-(7- chloro-3-ethyl- 1H-indazol-1-
yl)-1,2,4- oxadiazol-5-yl]- 1,4'-bipiperidin-1'- yl}ethanone
hydrochloride .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35 (3H, t, J =
7.6 Hz), 1.42-1.75 (2H, m), 1.95-2.20 (5H, m), 2.23-2.57 (5H, m),
2.95-3.23 (5H, m), 3.39-3.63 (4H, m), 3.89-4.02 (1H, m), 4.44-4.58
(1H, m), 7.39 (1H, t, J = 7.8 Hz), 7.64-7.71 (1H, m), 7.93-8.01
(1H, m), 10.90- 11.11 (1H, m). LC-MS, m/z; 457 [M + H]+ 241 Et H F
--Ms 4-[3-(3-ethyl-7- fluoro-1H- indazol-1-yl)- 1,2,4-oxadiazol-
5-yl]-1'- (methylsulfonyl)- 1,4'-bipiperidine .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 1.34 (3H, t, J = 7.6 Hz), 1.49 (2H, m),
1.75-1.84 (4H, m), 2.05-2.13 (2H, m), 2.31- 2.43 (3H, m), 2.70 (2H,
t, J = 11.1 Hz), 2.84 (3H, s), 2.89 (2H, d, J = 11.1 Hz), 3.03 (2H,
q, J = 7.5 Hz), 3.08-3.17 (1H, m), 3.58 (2H, d, J = 12.0 Hz),
7.34-7.39 (1H, m), 7.42-7.48 (1H, m), 7.77 (1H, d, J = 7.7 Hz).
LC-MS, m/z; 477 [M + H]+
Example 242
Preparation of
1-(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}--
1,4'-bipiperidin-1'-yl)-2-hydroxyethanone
##STR00312##
[0742]
4-{3-[7-Fluoro-3-(propan-2-yl)-11'-indazol-1-yl]-1,2,4-oxadiazol-5--
yl}-1,4'-bipiperidine dihydrochloride (130 mg) was dissolved in
dichloromethane (4 ml). To the solution were added triethylamine
(186 .mu.l) and acetoxyacetyl chloride (43 .mu.l), and the mixture
was stirred at room temperature for 20 minutes. To the reaction
solution was added saturated sodium bicarbonate (10 ml), and the
mixture was extracted with ethyl acetate (20 ml). The organic layer
was washed with water (10 ml), dried over sodium sulfate and
filtered. The filtrate was concentrated under reduced pressure. The
residue was suspended in methanol (2 ml), 2 N sodium hydroxide (15
.mu.l) was added thereto, and the mixture was stirred at room
temperature for 20 minutes. To the reaction mixture was added ethyl
acetate (20 ml), and the mixture was washed with water (10
ml.times.2). The organic layer was dried over sodium sulfate and
concentrated under reduced pressure, and the residue was purified
by silica-gel chromatography (column; Hi-Flash.TM. Amino Column,
developing solvent: ethyl acetate) to give the title compound (93
mg) as a white solid.
Free Form
[0743] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.24-1.48 (8H, m),
1.68-1.86 (4H, m), 2.04-2.16 (2H, m), 2.27-2.41 (2H, m), 2.49-2.66
(2H, m), 2.83-2.99 (3H, m), 3.08-3.20 (1H, m), 3.45-3.54 (1H, m),
3.65-3.76 (1H, m), 4.00-4.15 (2H, m), 4.32-4.42 (1H, m), 4.47 (1H,
t, J=5.4 Hz), 7.33-7.50 (2H, m), 7.83 (1H, d, J=7.7 Hz).
[0744] HCl salt was obtained by treatment with 1N HCl/diethyl
ether.
[0745] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.41 (6H, d, J=6.8 Hz),
1.49-1.78 (2H, m), 2.02-2.69 (7H, m), 2.82-3.61 (8H, m), 3.68-3.94
(1H, m), 4.00-4.19 (2H, m), 4.36-4.78 (2H, m), 7.33-7.53 (2H, m),
7.79-7.88 (1H, m), 10.84-11.13 (1H, m).
[0746] LC-MS, m/z; 471 [M+H]+
Preparations of Examples 243 to 244
##STR00313##
[0747] Wherein HX is hydrochloric acid or trifluoroacetic acid.
[0748] The compounds in the following table (i.e. Examples 243 to
244) were prepared in the same manner as in Example 242 except that
the
4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-1,4-
'-bipiperidine dihydrochloride was replaced with the corresponding
starting compound. Each of the hydrochlorides in the following
table was obtained by dissolving the resultant compound in
methylene chloride and then treating with 1N HCl/diethyl ether
solution.
TABLE-US-00037 TABLE 37 Ex. R.sup.3 R.sup.6 R.sup.7 Compound Name
.sup.1H-NMR/LC-MS, m/z 243 Et F H 1-{4-[3-(3- .sup.1H-NMR
(DMSO-d.sub.6) .delta.: ethyl-6- 1.34 (3H, t, J = 7.6 Hz),
fluoro-1H- 1.50-1.72 (2H, indazol-1- m), 2.13 (2H, d, J = 11.0 Hz),
yl)-1,2,4- 2.22-2.42 (4H, m), oxadiazol- 2.55-2.65 (1H, m),
5-yl]-1,4'- 2.99-3.06 (3H, m), bipiperidin-1'-yl}- 3.12-3.23 (2H,
m), 2- 3.44-3.57 (4H, m), 3.86 (1H, d, hydroxyethanone J = 14.1
Hz), hydrochloride 4.04-4.17 (2H, m), 4.50 (1H, d, J = 13.4 Hz),
7.26-7.33 (1H, m), 7.87-7.93 (1H, m), 7.99-8.04 (1H, m), 10.73 (1H,
s). LC-MS, m/z; 457 [M + H]+ 244 Et H F 1-{4-[3-(3- .sup.1H-NMR
(DMSO-d.sub.6) .delta.: ethyl-7- 1.42 (3H, t, J = 7.6 Hz),
fluoro-1H- 1.56-1.80 (2H, indazol-1- m), 2.22 (2H, d, J = 11.0 Hz),
yl)-1,2,4- 2.35-2.45 (4H, m), oxadiazol- 2.68 (1H, t, 5-yl]-1,4'- J
= 12.2 Hz), bipiperidin-1'-yl}- 3.01-3.14 (3H, m), 2- 3.18-3.28
(2H, m), hydroxyethanone 3.50-3.64 (4H, m), hydrochloride 3.93 (1H,
d, J = 12.2 Hz), 4.13-4.23 (2H, m), 4.57 (1H, d, J = 12.0 Hz),
7.42-7.49 (1H, m), 7.50-7.58 (1H, m), 7.85 (1H, d, J = 7.8 Hz),
11.15 (1H, s). LC-MS, m/z; 457 [M + H]+
Preparations of Examples 245 to 246
##STR00314##
[0749] Wherein HX is hydrochloric acid or trifluoroacetic acid.
[0750] The compounds in the following table (i.e. Examples 245 to
246) were prepared in the same manner as in Example 242 except that
the
4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-1,4-
'-bipiperidine dihydrochloride was replaced with the corresponding
starting compound. The hydrochloride in the following table was
obtained by dissolving the resultant compound in methylene chloride
and then treating with 1N HCl/diethyl ether solution.
TABLE-US-00038 TABLE 38 Ex. R.sup.3 R.sup.6 R.sup.7 Compound Name
.sup.1H-NMR/LC-MS, m/z 245 .sup.iPr H F 1-{4-[(4-{3-[7- .sup.1H-NMR
(CD.sub.3OD) .delta.: fluoro-3-(propan-2- 1.17-1.39 (3H, m),
yl)-1H- 1.48 (6H, d, J = 7.1 Hz), indazol-1-yl]- 1.80-3.22 (12H,
m), 1,2,4- 3.48-3.62 (9H, m), oxadiazol-5- 7.29-7.40 (2H, m),
yl}piperidin-1- 7.71-7.78 (1H, m). yl)methyl]piperidin- LC-MS, m/z;
1-yl}-2- 485 [M + H]+ hydroxyethanone hydrochloride 246 Et H F
1-[4-({4-[3-(3-ethyl- .sup.1H-NMR (DMSO-d.sub.6) .delta.:
7-fluoro-1H- 0.89-1.04 (2H, m), indazol- 1.34 (3H, t, J = 7.5 Hz),
1-yl)-1,2,4- 1.68-1.83 (5H, m), oxadiazol-5- 2.06-2.15 (6H, m),
yl]piperidin-1- 2.58-2.66 (1H, m), yl}methyl)piperidin- 2.81-2.95
(3H, m), 3.03 (2H, 1-yl]-2- q, J = 7.6 Hz), hydroxyethanone
3.10-3.18 (1H, m), 3.62 (1H, d, J = 11.1 Hz), 4.04 (2H, t, J = 5.4
Hz), 4.32 (1H, d, J = 11.1 Hz), 4.41 (1H, t, J = 5.4 Hz), 7.34-7.40
(1H, m), 7.42-7.48 (1H, m), 7.75-7.79 (1H, m). LC-MS, m/z; 471 [M +
H]+
Example 247
Preparation of
1-[(3R)-3-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-
piperidin-1-yl}methyl)pyrrolidin-1-yl]-2-hydroxyethanone
##STR00315##
[0752] The title compound was prepared in the same manner as in
Example 242 except that the
4-[(3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl]-1,-
4'-bipiperidine dihydrochloride was replaced with
3-ethyl-7-fluoro-1-(5-{1-[(3S)-pyrrolidin-3-ylmethyl]piperidin-4-yl}-1,2,-
4-oxadiazol-3-yl)-1H-indazole dihydrochloride.
[0753] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (3H, t, J=7.6 Hz),
1.56-1.90 (2H, m), 1.96-2.29 (7H, m), 2.29-2.62 (3H, m), 2.84-3.17
(5H, m), 3.18-3.61 (3H, m), 3.73 (1H, m), 4.09 (2H, d, J=3.7 Hz),
7.20-7.33 (2H, m), 7.54 (1H, m).
[0754] LC-MS, m/z; 457 [M+H]+
Example 248
Preparation of 1-{(3R)-3-[(4-{3-[7-fluoro-3-(propan-1)
1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}piperidin-1-yl)methyl]pyrrolidin-1--
yl}-2-hydroxyethanone hydrochloride
##STR00316##
[0756] An intermediate was prepared in the same manner as in
Example 242 except that the
4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-1,4-
'-bipiperidine dihydrochloride was replaced with
7-fluoro-3-(propan-2-yl)-1-(5-{1-[(3S)-pyrrolidin-3-ylmethyl]piperidin-4--
yl}-1,2,4-oxadiazol-3-yl)-1H-indazole dihydrochloride, and then the
intermediate was dissolved in methylene chloride and treated with
1N HCl/diethyl ether solution to give the title compound of
hydrochloride.
[0757] .sup.1H-NMR (CD.sub.3OD) .delta.: 1.48 (6H, d, J=7.0 Hz),
1.62-2.90 (3H, m), 3.08-4.17 (19H, m), 7.32-7.36 (2H, m), 7.72-7.75
(1H, m).
[0758] LC-MS, m/z; 471[M+H]+
Preparations of Examples 249 to 250
##STR00317##
[0759] Wherein HX is hydrochloric acid or trifluoroacetic acid.
[0760] The compounds in the following table (i.e. Examples 249 to
250) were prepared in the same manner as in Example 242 except that
the
4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-1,4-
'-bipiperidine dihydrochloride was replaced with the corresponding
starting compound. The hydrochloride in the following table was
obtained by dissolving the resultant compound in methylene chloride
and then treating with 1N HCl/diethyl ether solution.
TABLE-US-00039 TABLE 39 Ex. R.sup.3 R.sup.6 R.sup.7 Compound Name
.sup.1H-NMR/LC-MS, m/z 249 .sup.iPr H F 1-{3-[(4-{3-[7- .sup.1H-NMR
(CD.sub.3OD) .delta.: fluoro-3-(propan- 1.47 (6H, d, J = 7.0 Hz),
2-yl)-1H-indazol- 1.73-3.13 (4H, m), 1-yl]-1,2,4- 3.24-4.59 (16H
m), oxadiazol-5- 7.32-7.36 (2H, m), yl}piperidin-1- 7.72-7.75 (1H,
m). yl)methyl]azetidin LC-MS, m/z; 457 [M + H]+ -1-yl}-2-
hydroxyethanone hydrochloride 250 Et H F 1-[3-({4-[3- .sup.1H-NMR
(DMSO-d.sub.6) .delta.: (3-ethyl- 1.34 (3H, t, J = 7.6 Hz),
7-fluoro-1H- 1.78 (2H, q, J = 11.0 Hz), indazol- 2.04-2.17 (4H, m),
2.53 (2H, 1-yl)-1,2,4- d, J = 6.3 Hz), oxadiazol-5- 2.81 (3H, br
s), 3.02 (2H, yl]piperidin-1- q, J = 7.6 Hz), yl}methyl)azetidin-
3.13-3.13 (1H, m), 1-yl]-2- 3.49 (1H, dd, J = 9.5, hydroxyethanone
5.6 Hz), 3.78 (1H, dd, J = 9.0, 5.6 Hz), 3.86 (2H, d, J = 6.1 Hz),
3.93 (1H, t, J = 9.0 Hz), 4.20 (1H, t, J = 8.5 Hz), 4.83 (1H, t, J
= 6.1 Hz), 7.33-7.39 (1H, m), 7.42-7.47 (1H, m), 7.77 (1H, d, J =
8.0 Hz). LC-MS, m/z; 443 [M + H]+
Example 251
Preparation of
1'-ethyl-4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-1,-
4'-bipiperidine dihydrochloride
##STR00318##
[0762] An intermediate was prepared in the same manner as in
Example 134 except that the
3-ethyl-6-fluoro-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and tetrahydropyrane-4-carboaldehyde were replaced
with the
3-ethyl-7-fluoro-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indaz-
ole trifluoroacetate and 1-ethyl-4-piperidinone, respectively, and
then the intermediate was dissolved in methylene chloride and then
treated with 1N HCl/diethyl ether to give the title compound (60
mg) as a white solid.
[0763] LC-MS, m/z; 427 [M+H]+
Example 252
Preparation of
(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-1,-
4'-bipiperidin-1'-yl)(oxetan-3-yl)methanone
##STR00319##
[0765]
4-{3-[7-Fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-y-
l}-1,4'-bipiperidine dihydrochloride (120 mg) was dissolved in
dimethylformamide (4 ml). To the solution were added triethylamine
(276 .mu.l), 3-oxetanecarboxylic acid (56 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (114
mg) and 1-hydroxybenzotriazole (34 mg), and the mixture was stirred
at room temperature overnight. To the reaction solution was added
ethyl acetate (20 ml), and the mixture was washed with water (10
ml.times.2). The organic layer was dried over sodium sulfate and
concentrated under reduced pressure. The residue was purified by
silica-gel chromatography (column; Hi-Flash.TM. Amino Column,
developing solvent: ethyl acetate) to give the title compound (15
mg) as a colorless oil.
[0766] LC-MS, m/z; 497 [M+H]+
Example 253
Preparation of
2,2-difluoro-1-(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxa-
diazol-5-yl}-1,4'-bipiperidin-1'-yl)ethanone
##STR00320##
[0768]
4-{3-[7-Fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-y-
l}-1,4'-bipiperidine dihydrochloride (120 mg) was dissolved in
dimethylformamide (4 ml). To the solution were added triethylamine
(276 .mu.l), 2,2-difluoroacetic acid (52 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (114
mg) and 1-hydroxybenzotriazole (34 mg), and the mixture was stirred
at room temperature overnight. To the reaction solution was added
ethyl acetate (20 ml), and the mixture was washed with water (10
ml.times.2). The organic layer was dried over sodium sulfate and
concentrated under reduced pressure. The residue was purified by
silica-gel chromatography (column; Hi-Flash.TM. Amino Column,
developing solvent: ethyl acetate) to give the title compound (72
mg) as a colorless oil.
[0769] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44-1.69 (9H, m),
1.85-2.11 (4H, m), 2.13-2.25 (2H, m), 2.32-2.47 (2H, m), 2.55-2.81
(2H, m), 2.91-3.16 (4H, m), 3.39-3.56 (1H, m), 4.07-4.22 (1H, m),
4.48-4.61 (1H, m), 7.17-7.29 (2H, m), 7.54-7.63 (1H, m).
[0770] LC-MS, m/z; 491 [M+H]+
Example 254
Preparation of
4-{3-[7-fluoro-3-(propan-2-yl)-1,4-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-N--
methyl-1,4'-bipiperidine-1'-carboxamide
##STR00321##
[0772] 2.0 M Methylamine/THF (247 .mu.l) and carbodiimidazole (88
mg) were dissolved in THF (1.0 ml), and the solution was stirred at
room temperature for 1 hour. To the reaction solution were added
dropwise
4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-1,4-
'-bipiperidine dihydrochloride (120 mg) and triethylamine (103
.mu.l) in THF (2 ml), and the mixture was stirred at room
temperature overnight. To the reaction solution was added saturated
sodium bicarbonate aqueous solution (10 ml), and the mixture was
extracted with ethyl acetate (20 ml). The organic layer was washed
with brine, dried over sodium sulfate, and concentrated under
reduced pressure. The residue was purified by silica-gel
chromatography (column; Hi-Flash.TM. Amino Column, developing
solvent: ethyl acetate) to give the title compound (104 mg) as a
colorless oil.
[0773] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.37-1.59 (8H, m),
1.76-1.90 (2H, m), 1.92-2.59 (7H, m), 2.67-2.86 (5H, m), 2.93-3.12
(3H, m), 3.40-3.53 (1H, m), 3.91-4.07 (2H, m), 4.44-4.58 (1H, m),
7.17-7.30 (2H, m), 7.54-7.63 (1H, m).
[0774] LC-MS, m/z; 470 [M+H]+
Example 255
Preparation of
(2R)-2-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]pip-
eridin-1-yl}methyl)-N-methylpyrrolidine-1-carboxamide
##STR00322##
[0776] The title compound was prepared in the same manner as in
Example 254 except that the
4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-1,4-
'-bipiperidine dihydrochloride was replaced with
3-ethyl-7-fluoro-1-(5-{1-[(2R)-pyrrolidin-2-ylmethyl]piperidin-4-yl}-1,2,-
4-oxadiazol-3-yl)-1H-indazole dihydrochloride.
[0777] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (3H, t, J=7.6 Hz),
1.59 (1H, m), 1.77 (2H, m), 1.92-2.11 (3H, m), 2.15-2.31 (3H, m),
2.32-2.45 (2H, m), 2.54 (1H, dd, J=13.4, 8.6 Hz), 2.78 (3H, d,
J=3.7 Hz), 2.97 (1H, m), 3.02-3.20 (4H, m), 3.28 (1H, m), 3.66-3.86
(2H, m), 7.20-7.33 (2H, m), 7.54 (1H, s), 7.77 (1H, bs).
[0778] LC-MS, m/z; 456 [M+H]+
Example 256
Preparation of
(3R)-3-({4-[3-(3-ethyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]pip-
eridin-1-yl}methyl)-N-methylpyrrolidine-1-carboxamide
##STR00323##
[0780] The title compound was prepared in the same manner as in
Example 254 except that the
4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-1,4-
'-bipiperidine dihydrochloride was replaced with
3-ethyl-7-fluoro-1-(5-{1-[(3S)-pyrrolidin-3-ylmethyl]piperidin-4-yl}-1,2,-
4-oxadiazol-3-yl)-1H-indazole dihydrochloride.
[0781] LC-MS, m/z; 456 [M+H]+
Example 257
Preparation of methyl
4-{3-[3-(3-ethyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]azetidin-1-yl}pipe-
ridine-1-carboxylate
##STR00324##
[0783] The compound in the following table (Example 257) was
prepared in the same manner as in Example 168 except that the
3-ethyl-1-(5-{1-[2-(piperidin-4-yl)ethyl]piperidin-4-yl}-1,2,4-oxadiazol--
3-yl)-1H-indazole bis(trifluoroacetate) was replaced with
3-ethyl-1-{5-[1-(piperidin-4-yl)azetidin-3-yl]-1,2,4-oxadiazol-3-yl}-1H-i-
ndazole bis(trifluoroacetate). The free form of the compound in the
following table was obtained by omitting the conversion step into
hydrochloride in Example 168.
TABLE-US-00040 TABLE 40 .sup.1H NMR/ Ex. R.sup.3 R.sup.6 R.sup.7 R
Compound Name LC-MS, m/z 257 Et H H --CO.sub.2Me methyl 4-{3-[3-(3-
LC-MS, m/z; ethyl-1H-indazol-1- 411 [M + H]+ yl)-1,2,4-oxadiazol-5-
yl]azetidin-1- yl}piperidine-1- carboxylate
Example 258
Preparation of
1-(4-{3-[3-(3-ethyl-6-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]azetid-
in-1-yl}piperidin-1-yl)ethanone trifluoroacetate
##STR00325##
[0785]
1-[5-(Azetidin-3-yl)-1,2,4-oxadiazol-3-yl]-3-ethyl-6-fluoro-1H-inda-
zole hydrochloride (100 mg) was dissolved in methanol (10 ml). To
the solution were added 1-acetylpiperidin-4-one (56 mg), acetic
acid (24 mg) and sodium cyanoborohydride (41 mg), and the mixture
was stirred at room temperature overnight. The reaction solution
was filtered, the filtrate was concentrated, water was added
thereto, and the mixture was extracted with dichloromethane. The
organic layer was dried over sodium sulfate and concentrated under
reduced pressure. The residue was purified by reverse phase HPLC to
give the title compound (29 mg) as a white solid.
[0786] LC-MS, m/z; 413 [M+H]+
Example 259
Preparation of methyl
4-{3-[3-(3-ethyl-6-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]azetidin--
1-yl}piperidine-1-carboxylate trifluoroacetate
##STR00326##
[0788] The title compound was prepared in the same manner as in
Example 258 except that 1-acetylpiperidin-4-one was replaced with
methyl 4-oxopiperidine-1-carboxylate.
[0789] LC-MS, m/z; 429 [M+H]+
Example 260
Preparation of methyl
3-{3-[3-(3-ethyl-6-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]azetidin--
1-yl}pyrrolidine-1-carboxylate trifluoroacetate
##STR00327##
[0791] The title compound was prepared in the same manner as in
Example 258 except that the 1-acetylpiperidin-4-one was replaced
with methyl 3-oxopyrrolidine-1-carboxylate.
[0792] LC-MS, m/z; 415 [M+H]+
Example 261
Preparation of
3-{4-[3-(3-ethyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}pro-
pan-1-ol
##STR00328##
[0794] (1)
3-Ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate (120 mg) was suspended in N,N-dimethylformamide (3
ml). To the suspension were added
(3-bromopropoxy)(tert-butyl)dimethylsilane (103 mg) and potassium
carbonate (161 mg), and the mixture was refluxed overnight. The
reaction solution was cooled to room temperature and water was
added thereto. The mixture was extracted with ethyl acetate. The
organic layer was washed with water and brine, dried over sodium
sulfate, and filtered. The filtrate was concentrated under reduced
pressure, and the residue was purified by silica-gel chromatography
(column; Hi-Flash.TM. Amino column, developing solvent:
hexane/ethyl acetate=2:1) to give
1-{5-[1-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)piperidin-4-yl]-
-1,2,4-oxadiazol-3-yl}-3-ethyl-1H-indazole (103 mg) as a white
solid.
[0795] LC-MS, m/z; 470 [M+H]+
[0796] (2)
1-{5-[1-(3-{[Tert-butyl(dimethyl)silyl]oxy}propyl)piperidin-4-y-
l]-1,2,4-oxadiazol-3-yl}-3-ethyl-1H-indazole (100 mg) was dissolved
in dichloromethane (5 ml). To the solution was added 1N
tetrabutylammonium fluoride in tetrahydrofuran (0.3 ml), and the
mixture was stirred at 70.degree. C. for 4 hours. The reaction
solution was cooled to room temperature, water was added to the
reaction solution, and the mixture was extracted with ethyl
acetate. The organic layer was washed with brine, dried over sodium
sulfate and filtered, and the filtrate was concentrated under
reduced pressure. The residue was purified by silica-gel
chromatography (column; Hi-Flash.TM. Amino Column, developing
solvent: chloroform/methanol) to give the title compound (58 mg) as
a colorless oil.
[0797] LC-MS, m/z; 356 [M+H]+
Example 262
Preparation of
7-fluoro-1-{5-[1-(4-methoxycyclohexyl)piperidin-4-yl]-1,2,4-oxadiazol-3-y-
l}-3-(propan-2-yl)-1H-indazole
##STR00329##
[0799]
7-Fluoro-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-3-(propan-2-yl-
)-1H-indazole trifluoroacetate (250 mg) was dissolved in
dichloromethane (5 ml). To the solution were added
4-methoxycyclohexanone (145 mg) and sodium triacetoxyborohydride
(358 mg), and the mixture was stirred at room temperature for 2
days. To the reaction solution was added saturated sodium
bicarbonate (10 ml), and the mixture was extracted with ethyl
acetate (20 ml). The organic layer was washed with water (10
ml.times.2), dried over sodium sulfate, and concentrated under
reduced pressure. The residue was purified by silica-gel
chromatography (column; Hi-Flash.TM. Amino Column, developing
solvent: hexane/ethyl acetate=2:1) to give the title compound (184
mg) as a colorless oil.
[0800] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14-1.72 (11H, m),
1.76-2.61 (10H, m), 2.75-3.61 (8H, m), 7.15-7.30 (2H, m), 7.51-7.64
(1H, m).
[0801] LC-MS, m/z; 442 [M+H]+
Example 263
[0802] Preparations of (1S,2S) and
(1R,2R)-2-(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazo-
l-5-yl}piperidin-1-yl)cyclohexanol
##STR00330##
[0803] To a mixture of
7-fluoro-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-3-(propan-2-yl)-1H-i-
ndazole trifluoroacetate (120 mg) and ethanol (2.0 ml) were added
N,N-diisopropylethylamine (174 .mu.l) and
7-oxabicyclo[4.1.0]heptane (133 mg), and the mixture was stirred
under reflux for 2 days. The reaction solution was concentrated and
the residue was purified by silica-gel chromatography (column;
Hi-Flash.TM. Amino Column, developing solvent: hexane/ethyl
acetate=1:1) to give the title compound (106 mg) as a colorless
oil.
[0804] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.09-1.36 (4H, m),
1.42-1.58 (7H, m), 1.65-1.86 (3H, m), 1.90-2.35 (7H, m), 2.70-2.83
(2H, m), 2.96-3.11 (2H, m), 3.37-3.56 (2H, m), 7.18-7.30 (2H, m),
7.55-7.63 (1H, m). LC-MS, m/z; 428 [M+H]+
Example 264
[0805] Preparations of (1S,2S) and
(1R,2R)-2-(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazo-
l-5-yl}piperidin-1-yl)cyclopentanol
##STR00331##
[0806] The title compound was prepared in the same manner as in
Example 263 except that the 7-oxabicyclo[4.1.0]heptane was replaced
with 6-oxabicyclo[3.1.0]hexane.
[0807] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (6H, d, J=7.1 Hz),
1.53-1.75 (4H, m), 1.84-2.39 (9H, m), 2.53-2.63 (1H, m), 2.98-3.22
(3H, m), 3.43-3.54 (1H, m), 4.14 (1H, dd, J=13.0, 5.7 Hz),
7.18-7.29 (2H, m), 7.54-7.62 (1H, m).
[0808] LC-MS, m/z; 414 [M+H]+
Example 265
Preparation of
N-(2-{4-[3-(3-methyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl-
}ethyl)benzamide
##STR00332##
[0810] The title compound (13 mg) as a white solid was prepared in
the same manner as in Example 168 except that the
3-ethyl-1-(5-{1-[2-(piperidin-4-yl)ethyl]piperidin-4-yl}-1,2,4-oxadiazol--
3-yl)-1H-indazole bis(trifluoroacetate) and methyl chloroformate
were replaced with
2-{4-[3-(3-methyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}et-
hanamine bis(trifluoroacetate) and benzoyl chloride, respectively,
and the conversion step into hydrochloride was omitted.
[0811] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.81-1.90 (2H, m), 2.11
(2H, d, J=10.7 Hz), 2.20 (2H, t, J=10.7 Hz), 2.51-2.54 (2H, m),
2.60 (3H, s), 2.95 (2H, d, J=11.8 Hz), 3.10-3.17 (1H, m), 3.40 (2H,
q, J=6.6 Hz), 7.37-7.53 (4H, m), 7.65 (1H, m), 7.83 (2H, d, J=6.8
Hz), 7.91 (1H, d, J=7.8 Hz), 8.20 (1H, d, J=8.5 Hz), 8.41 (1H, t,
J=5.6 Hz).
[0812] LC-MS, m/z; 431 [M+H]+
Preparations of Examples 266 to 268
##STR00333##
[0813] Wherein HX is hydrochloric acid or trifluoroacetic acid.
[0814] The compounds in the following table (i.e. Examples 266 to
268) were prepared in the same manner as in Example 265 except that
the
2-{4-[3-(3-methyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}et-
hanamine bis(trifluoroacetate) and benzoyl chloride were replaced
with the corresponding starting compound and acid chloride (defined
as R--Cl), respectively.
TABLE-US-00041 TABLE 41 Ex. R.sup.3 R.sup.6 n R Compound Name
.sup.1H-NMR/LC-MS, m/z 266 Me H 1 --Ms N-(2-{4-[3-(3- .sup.1H-NMR
(DMSO-d.sub.6) .delta.: methyl-1H- 1.80-1.90 (2H, m),
indazol-1-yl)- 2.08-2.20 (4H, m), 1,2,4-oxadiazol- 2.44 (2H, t, J =
6.7 Hz), 5-yl]piperidin-1- 2.60 (3H, yl}ethyl)methanesulfonamide
s), 2.87-2.93 (5H, m), 3.05-3.17 (3H, m), 6.88 (1H, s), 7.39 (1H,
m), 7.65 (1H, m), 7.91 (1H, d, J = 7.8 Hz), 8.20 (1H, d, J = 8.5
Hz). LC-MS, m/z; 405 [M + H]+ 267 Me H 2 --CO.sub.2Me methyl
(3-{4-[3- LC-MS, m/z; (3-methyl-1H- 399 [M + H]+ indazol-1-yl)-
1,2,4-oxadiazol- 5-yl]piperidin-1- yl}propyl)carbamate 268 Et F 1
--CO.sub.2Me methyl (2-{4-[3- .sup.1H-NMR (CDCl.sub.3) .delta.:
(3-ethyl-6- 1.44 (3H, t, J = 7.6 Hz), fluoro-1H- 1.97-2.27 (6H, m),
2.52 (2H, indazol-1-yl)- t, J = 5.9 Hz), 1,2,4-oxadiazol- 2.89-3.13
(5H, m), 5-yl]piperidin-1- 3.24-3.39 (2H, m), yl}ethyl)carbamate
3.69 (3H, s), 5.05-5.29 (1H, m), 7.08 (1H, td, J = 8.9, 2.2 Hz),
7.70 (1H, dd, J = 8.7, 5.0 Hz), 7.98 (1H, dd, J = 9.3, 2.2 Hz).
LC-MS, m/z; 417 [M + H]+
Example 269
Preparation of methyl
methyl(3-{4-[3-(3-methyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidin--
1-yl}propyl)carbamate
##STR00334##
[0816] The title compound (57 mg) as a white solid was prepared in
the same manner as in Example 097 except that the
3-ethyl-6-fluoro-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and ethyl iodide were replaced with
3-methyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1,4-indazole
trifluoroacetate and methyl(3-chloropropyl)methylcarbamate,
respectively, and the conversion step into hydrochloride was
omitted.
[0817] LC-MS, m/z; 413 [M+H]+
Preparations of Examples 270 to 271
##STR00335##
[0818] Wherein HX is hydrochloric acid or trifluoroacetic acid.
[0819] The compounds in the following table (i.e. Examples 270 to
271) were prepared in the same manner as in Example 265 except that
the
2-{4-[3-(3-methyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}et-
hanamine bis(trifluoroacetate) and benzoyl chloride were replaced
with the corresponding starting compound and acetic anhydride,
respectively.
TABLE-US-00042 TABLE 42 .sup.1H NMR/LC- Ex. R.sup.6 Compound Name
MS, m/z 270 H N-(2-{3-[3-(3-ethyl-1H-indazol-1- LC-MS, m/z;
yl)-1,2,4-oxadiazol-5-yl]azetidin- 355 [M + H]+
1-yl}ethyl)acetamide 271 F N-(2-{3-[3-(3-ethyl-6-fluoro-1H- LC-MS,
m/z; indazol-1-yl)-1,2,4-oxadiazol-5- 373 [M + H]+
yl]azetidin-1-yl}ethyl)acetamide
Examples 272 to 273
Preparations of
3-ethyl-1-{5-[cis-4-(morpholin-4-yl)cyclohexyl]-1,2,4-oxadiazol-3-yl}-1H--
indazole and
3-ethyl-1-{5-[trans-4-(morpholin-4-yl)cyclohexyl]-1,2,4-oxadiazol-3-yl}-1-
H-indazole
##STR00336##
[0821]
4-[3-(3-Ethyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]cyclohexanone
(160 mg) was dissolved in dichloromethane (10 ml). To the solution
was added morpholine (46 mg), and the mixture was stirred for 10
minutes. To the reaction mixture was further added acetic acid (40
mg), and the mixture was stirred for 30 minutes. To the resultant
mixture was added triacetoxysodium borohydride (164 mg), and the
mixture was stirred at room temperature overnight. After the
completion of the reaction, 1N potassium hydroxide aqueous solution
was added to the reaction mixture, and the mixture was extracted
with ethyl acetate. The organic layer was washed with brine, dried
over sodium sulfate and filtered, and the filtrate was concentrated
under reduced pressure. The residue was purified by silica-gel
chromatography (column; Hi-Flash.TM. Amino Column, developing
solvent: hexane/ethyl acetate) to give the title compounds as a
colorless oil of cis form: 75 mg and trans form: 30 mg,
respectively.
[0822] cis form: .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.36 (3H, t,
J=7.6 Hz), 1.60-1.86 (6H, m), 2.10-2.30 (3H, m), 2.42 (2H, s), 3.03
(2H, q, J=7.6 Hz), 3.33-3.41 (3H, m), 3.55 (4H, m), 7.36-7.41 (1H,
m), 7.62 (1H, m), 7.94 (1H, d, J=7.7 Hz), 8.20 (1H, d, J=8.3
Hz).
[0823] LC-MS, m/z; 382 [M+H]+
[0824] trans form: LC-MS, m/z; 382 [M+H]+
Example 274
Preparation of
3-ethyl-6-fluoro-1-{5-[cis-4-(pyrrolidin-1-yl)cyclohexyl]-1,2,4-oxadiazol-
-3-yl}-1H-indazole
##STR00337##
[0826] The title compound was prepared in the same manner as in
Example 272 except that the morpholine was replaced with
pyrrolidine.
[0827] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (3H, t, J=7.7 Hz),
1.67-1.96 (10H, m), 2.13-2.23 (1H, m), 2.31-2.44 (2H, m), 2.48-2.61
(4H, m), 3.07 (2H, q, J=7.6 Hz), 3.16-3.26 (1H, m), 7.07 (1H, td,
J=8.9, 2.2 Hz), 7.69 (1H, dd, J=8.7, 5.0 Hz), 7.98 (1H, dd, J=9.4,
2.3 Hz). LC-MS, m/z; 384 [M+H]+
Preparations of Examples 275 to 278
##STR00338##
[0829] The compounds in the following table (i.e. Examples 275 to
278) were prepared in the same manner as in Example 272 except that
the
4-[3-(3-ethyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]cyclohexanone
and morpholine were replaced with the corresponding starting
compound
"3-[3-(3-ethyl-6-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]cyclobutano-
ne" and amine, respectively.
TABLE-US-00043 TABLE 43 Ex. X Compound Name .sup.1H-NMR/LC-MS, m/z
275 ##STR00339## cis-3-[3-(3-ethyl- 6-fluoro-1H- indazol-1-yl)-
1,2,4-oxadiazol-5- yl]-N-(tetrahydro- 2H-pyran-4-ylmethyl)
cyclobutanamine .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21- 1.58 (6H,
m), 1.60-1.77 (3H, m), 2.28 (2H, m), 2.49 (2H, d, J = 6.2 Hz), 2.84
(2H, m), 3.07 (2H, q, J = 7.6 Hz), 3.32-3.55 (4H, m), 3.99 (2H, dd,
J = 11.0, 3.9 Hz), 7.09 (1H, m), 7.71 (1H, m), 7.98 (1H, m). LC-MS,
m/z; 400 [M + H]+ 276 ##STR00340## 3-ethyl-6-fluoro- 1-{5-[3-(3-
methoxyazetidin-1- yl)cyclobutyl]- 1,2,4-oxadiazol-3-
yl}-1H-indazole .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (3H, t, J =
7.6 Hz), 2.28- 2.67 (4H, m), 2.95-3.14 (4H, m), 3.25-3.67 (7H, m),
4.07 (1H, s), 7.08 (1H, m), 7.70 (1H, m), 7.98 (1H, m). LC-MS, m/z;
372 [M + H]+ 277 ##STR00341## N-{cis-3-[3-(3- ethyl-6-fluoro-1H-
indazol-1-yl)- 1,2,4-oxadiazol-5- yl]cyclobutyl} cyclopentaneamine
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.38- 1.84 (9H, m), 2.13-2.40
(4H, m), 2.79 (2H, m), 3.07 (2H, q, J = 7.6 Hz), 3.23-3.54 (3H, m),
7.09 (1H, m), 7.70 (1H, m), 7.98 (1H, m). LC-MS, m/z; 370 [M + H]+
278 ##STR00342## cis-N-ethyl-3-[3- (3-ethyl-6-fluoro-
1H-indazol-1-yl)- 1,2,4-oxadiazol-5- yl]cyclobutanamine .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.14 (3H, t, J = 7.2 Hz), 1.44 (3H, t, J =
7.6 Hz), 2.30 (2H, s), 2.67 (2H, q, J = 7.2 Hz), 2.85 (2H, s), 3.08
(2H, q, J = 7.6 Hz), 3.45 (2H, s), 7.09 (1H, m), 7.71 (1H, m), 7.98
(1H, m). LC-MS, m/z; 330 [M + H]+
Preparations of Examples 279 to 281
##STR00343##
[0831] The compounds in the following table (i.e. Examples 279 to
281) were prepared in the same manner as in Example 097 except that
the
3-ethyl-6-fluoro-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and ethyl iodide were replaced with the
corresponding starting compound and butyl bromide, respectively.
Each free form of the compounds in the following table was obtained
by omitting the conversion step into hydrochloride in Example
097.
TABLE-US-00044 TABLE 44 .sup.1H-NMR/ Ex. R.sup.3 Q Compound Name
LC-MS, m/z 279 Cl ##STR00344## 1-[5-(1-butylpiperidin-4-
yl)-1,3,4-oxadiazol-2- yl]-3-chloro-1H-indazole LC-MS, m/z; 360 [M
+ H]+ 280 Cl ##STR00345## 1-[3-(1-butylpiperidin-4-
yl)-1,2,4-oxadiazol-5- yl]-3-chloro-1H-indazole hydrochloride
LC-MS, m/z; 360 [M + H]+ 281 .sup.iPr ##STR00346##
1-[3-(1-butylpiperidin-4- yl)isoxazol-5-yl]-3-
(propan-2-yl)-1H-indazole .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.88
(3H, t, J = 7.3 Hz), 1.24-1.33 (2H, m), 1.37-1.45 (8H, m),
1.68-1.77 (2H, m), 1.89-2.01 (4H, m), 2.27 (2H, t, J = 7.3 Hz),
2.65-2.74 (1H, m), 2.91 (2H, d, J = 11.5 Hz), 3.43-3.50 (1H, m),
6.52 (1H, s), 7.37 (1H, t, J = 7.6 Hz), 7.60-7.64 (1H, m),
7.98-8.01 (2H, m). LC-MS, m/z; 367 [M + H]+
Example 282
Preparation of
1-{5-[1-(2-phenylethyl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}-1H-pyrrolo[2-
,3-b]pyridine
##STR00347##
[0833] The title compound was prepared in the same manner as in
Example 097 except that the
3-ethyl-6-fluoro-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and ethyl iodide were replaced with
1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine
trifluoroacetate and phenethyl bromide, respectively, and the
conversion step into hydrochloride was omitted.
[0834] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.99-2.33 (6H, m),
2.59-2.70 (2H, m), 2.79-2.89 (2H, m), 2.99-3.13 (3H, m), 6.69 (1H,
d, J=3.9 Hz), 7.17-7.25 (4H, m), 7.26-7.33 (2H, m), 7.88 (1H, d,
J=3.9 Hz), 7.96 (1H, m), 8.57 (1H, m).
[0835] LC-MS, m/z; 374 [M+H]+
Preparations of Examples 283 to 284
##STR00348##
[0836] Wherein HX is hydrochloric acid or trifluoroacetic acid.
[0837] The compounds in the following table (i.e. Examples 283 to
284) were prepared in the same manner as in Example 097 except that
the
3-ethyl-6-fluoro-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and ethyl iodide were replaced with the
corresponding starting compound and butyl bromide, respectively,
and the conversion step into hydrochloride was omitted.
TABLE-US-00045 TABLE 45 Compound .sup.1H NMR/ Ex. Q Name LC-MS, m/z
283 ##STR00349## 1-[3-(1- butylpiperidin- 4-yl)-1,2,4-
oxadiazol-5-yl]- 1H-pyrrolo [2,3-b]pyridine LC-MS, m/z; 326 [M +
H]+ 284 ##STR00350## 1-[5-(1- butylpiperidin- 4-yl)-1,3,4-
oxadiazol-2-yl]- 1H-pyrrolo [2,3-b]pyridine LC-MS, m/z; 326 [M +
H]+
Example 285
Preparation of
1-{5-[1-(3-methoxypropyl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}-6-(propan--
2-yl)-1H-pyrrolo[2,3-b]pyridine
##STR00351##
[0839] The title compound was prepared in the same manner as in
Example 085 except that the
1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-3-(propan-2-yl)-1H-indazole
hydrochloride was replaced with
1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-6-(propan-2-yl)-1H-pyrrolo[2,-
3-b]pyridine hydrochloride.
[0840] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.39 (6H, d, J=6.8 Hz),
1.79 (2H, m), 1.95-2.21 (6H, m), 2.45 (2H, dd, J=8.4, 6.8 Hz),
2.91-3.06 (3H, m), 3.27 (1H, m), 3.34 (3H, s), 3.43 (2H, t, J=6.4
Hz), 6.62 (1H, d, J=3.9 Hz), 7.14 (1H, d, J=8.1 Hz), 7.78 (1H, d,
J=4.0 Hz), 7.86 (1H, d, J=8.1 Hz).
[0841] LC-MS, m/z; 384 [M+H]+
[0842] The compounds in the following table (i.e. Examples 286 to
297) were prepared in the same manner as in Example 001 or Example
012 except that the corresponding starting compound (which is
described in Reference Examples 116 to 127) was used.
##STR00352##
Wherein HX is hydrochloric acid or trifluoroacetic acid.
TABLE-US-00046 TABLE 46 .sup.1H-NMR/LC-MS, Ex. R.sup.3 R.sup.4
R.sup.5 R.sup.6 R.sup.7 Compound Name m/z 286 .sup.iPr Me H H H
4-methyl-1-[5- LC-MS, m/z; (piperidin-4- 326 [M + H]+ yl)-1,2,4-
oxadiazol-3-yl]- 3-(propan-2-yl)- 1H-indazole hydrochloride 287
.sup.iPr Cl H H H 4-chloro-1-[5- LC-MS, m/z; (piperidin-4- 346 [M +
H]+ yl)-1,2,4- oxadiazol-3-yl]- 3-(propan-2-yl)- 1H-indazole
hydrochloride 288 .sup.iPr H Me H H 5-methyl-1-[5- LC-MS, m/z;
(piperidin-4- 326 [M + H]+ yl)-1,2,4- oxadiazol-3-yl]-
3-(propan-2-yl)- 1H-indazole hydrochloride 289 .sup.iPr H Cl H H
5-chloro-1-[5- LC-MS, m/z; (piperidin-4- 346 [M + H]+ yl)-1,2,4-
oxadiazol-3-yl]- 3-(propan-2-yl)- 1H-indazole hydrochloride 290
.sup.iPr H MeO H H 5-methoxy-1-[5- LC-MS, m/z; (piperidin-4- 342 [M
+ H]+ yl)-1,2,4- oxadiazol-3-yl]- 3-(propan-2-yl)- 1H-indazole
hydrochloride 291 Et H H Me H 3-ethyl-6- LC-MS, m/z; methyl-1-[5-
312 [M + H]+ (piperidin-4- yl)-1,2,4- oxadiazol-3-yl]- 1H-indazole
hydrochloride 292 .sup.iPr H H Me H 6-methyl-1-[5- LC-MS, m/z;
(piperidin-4- 326 [M + H]+ yl)-1,2,4- oxadiazol-3-yl]-
3-(propan-2-yl)- 1H-indazole hydrochloride 293 .sup.iPr H H Cl H
6-chloro-1-[5- LC-MS, m/z; (piperidin-4- 346 [M + H]+ yl)-1,2,4-
oxadiazol-3-yl]- 3-(propan-2-yl)- 1H-indazole hydrochloride 294
.sup.iPr H H H Me 7-methyl-1-[5- LC-MS, m/z; (piperidin-4- 326 [M +
H]+ yl)-1,2,4- oxadiazol-3-yl]- 3-(propan-2-yl)- 1H-indazole
hydrochloride 295 .sup.iPr H H H MeO 7-methoxy-1-[5- LC-MS, m/z;
(piperidin-4- 342 [M + H]+ yl)-1,2,4- oxadiazol-3-yl]-
3-(propan-2-yl)- 1H-indazole hydrochloride 296 Et H H F F
3-ethyl-6,7- LC-MS, m/z; difluoro-1-[5- 334 [M + H]+ (piperidin-4-
yl)-1,2,4- oxadiazol-3-yl]- 1H-indazole hydrochloride 297 .sup.iPr
H H F F 6,7-difluoro-1- LC-MS, m/z; [5-(piperidin-4- 348 [M + H]+
yl)-1,2,4- oxadiazol-3-yl]- 3-(propan-2-yl)- 1H-indazole
hydrochloride
[0843] The compounds in the following table (i.e. Examples 298 to
307) were prepared in the same manner as in Example 001 or Example
012 except that the tert-butyl
4-[3-(3-ethyl-6-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidine-1-
-carboxylate of Example 001 or the tert-butyl
4-{3-[3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}piperidine-1--
carboxylate of Example 012 was replaced with the corresponding
starting compound.
##STR00353##
Wherein (B-2) means each cyclic amino structure shown in the
following table, HX is hydrochloric acid or trifluoroacetic acid,
and the Boc group is attached to the nitrogen atom in the cyclic
amine of (B-2).
TABLE-US-00047 TABLE 47 .sup.1H-NMR/LC-MS, Ex. R.sup.3 R.sup.6
R.sup.7 (B-2) Compound Name m/z 298 .sup.iPr H F ##STR00354##
7-fluoro-3-(propan- 2-yl)-1-[5- (pyrrolidin-3-yl)-
1,2,4-oxadiazol-3- yl]-1H-indazole hydrochloride LC-MS, m/z; 316 [M
+ H]+ 299 .sup.iPr H F ##STR00355## 4-{3-[7-fluoro-3-
(propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}piperidin-4-ol hydrochloride LC-MS, m/z; 346 [M + H]+ 300
.sup.iPr H F ##STR00356## 1-[5-(8- azabicyclo[3.2.1]oct-
3-yl)-1,2,4- oxadiazol-3-yl]-7- fluoro-3-(propan-2- yl)-1H-indazole
trifluoroacetate LC-MS, m/z; 356 [M + H]+ 301 .sup.iPr H F
##STR00357## 7-fluoro-1-[5-(2- methylpiperidin-4- yl)-1,2,4-
oxadiazol-3-yl]-3- (propan-2-yl)-1H- indazole trifluoroacetate
LC-MS, m/z; 344 [M + H]+ 302 .sup.iPr H F ##STR00358##
1-[5-(azetidin-3- ylmethyl)-1,2,4- oxadiazol-3-yl]-7-
fluoro-3-(propan-2- yl)-1H-indazole trifluoroacetate LC-MS, m/z;
316 [M + H]+ 303 .sup.iPr H F ##STR00359## 7-fluoro-1-[5-
(piperidin-4- ylmethyl)-1,2,4- oxadiazol-3-yl]-3- (propan-2-yl)-1H-
indazole trifluoroacetate LC-MS, m/z; 344 [M + H]+ 304 .sup.iPr H F
##STR00360## 7-fluoro-3-(propan- 2-yl)-1-{5-[(3R)- pyrrolidin-3-
ylmethyl]-1,2,4- oxadiazol-3-yl}-1H- indazole trifluoroacetate
LC-MS, m/z; 330 [M + H]+ 305 .sup.iPr H F ##STR00361##
7-fluoro-3-(propan- 2-yl)-1-{5-[(3S)- pyrrolidin-3-
ylmethyl]-1,2,4- oxadiazol-3-yl}-1H- indazole trifluoroacetate
LC-MS, m/z; 330 [M + H]+ 306 Et H F 3-ethyl-7-fluoro-1- {5-[(3S)-
pyrrolidin-3- ylmethyl]-1,2,4- oxadiazol-3-yl}-1H- indazole
trifluoroacetate No data 307 .sup.iPr F H 6-fluoro-3-(propan-
2-yl)-1-{5-[(3S)- pyrrolidin-3- ylmethyl]-1,2,4-
oxadiazol-3-yl}-1H- indazole trifluoroacetate No data
[0844] The compounds in the following table (i.e. Reference
Examples 308 to 311) were prepared in the same manner as in Example
028 except that the
3-ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and
(S)-(-)-1-tert-butoxycarbonyl-2-pyrrolidinecarbaldehyde were
replaced with the corresponding starting compound and tert-butyl
4-oxopiperidine-1-carboxylate, respectively.
##STR00362##
Wherein HX is hydrochloric acid or trifluoroacetic acid.
TABLE-US-00048 TABLE 48 Ex. R.sup.3 R.sup.6 R.sup.7 Compound Name
LC-MS, m/z 308 .sup.iPr H H tert-butyl 4-{3-[3-(propan-2- LC-MS,
m/z; yl)-1H-indazol-1-yl]-1,2,4- 495 [M + H]+ oxadiazol-5-yl}-1,4'-
bipiperidine-1'-carboxylate 309 .sup.iPr Me H tert-butyl
4-{3-[6-methyl-3- LC-MS, m/z; (propan-2-yl)-1H-indazol-1- 509 [M +
H]+ yl]-1,2,4-oxadiazol-5-yl}- 1,4'-bipiperidine-1'- carboxylate
.sup. 310.sup.1) Et F F tert-butyl 4-[3-(3-ethyl-6,7- LC-MS, m/z;
difluoro-1H-indazol-1-yl)- 517 [M + H]+ 1,2,4-oxadiazol-5-yl]-1,4'-
bipiperidine-1'-carboxylate .sup. 311.sup.1) .sup.iPr F F
tert-butyl 4-{3-[6,7-difluoro- LC-MS, m/z;
3-(propan-2-yl)-1H-indazol-1- 531 [M + H]+
yl]-1,2,4-oxadiazol-5-yl}- 1,4'-bipiperidine-1'- carboxylate
.sup.1)Titanium tetraisopropoxide was added to the reaction
system.
[0845] The compounds in the following table (i.e. Examples 312 to
315) were prepared in the same manner as in Example 028 except that
the 3-ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and
(S)-(-)-1-tert-butoxycarbonyl-2-pyrrolidinecarbaldehyde were
replaced with the corresponding starting compound and tert-butyl
3-formylazetidine-1-carboxylate, respectively.
##STR00363##
Wherein HX is hydrochloric acid or trifluoroacetic acid.
TABLE-US-00049 TABLE 49 Ex. R.sup.3 R.sup.6 R.sup.7 Compound Name
LC-MS, m/z 312 .sup.iPr H H tert-butyl 3-[(4-{3-[3- LC-MS, m/z;
(propan-2-yl)-1H-indazol-1- 481 [M + H]+ yl]-1,2,4-oxadiazol-5-
yl}piperidin-1- yl)methyl]azetidine-1- carboxylate 313 .sup.iPr Me
H tert-butyl 3-[(4-{3-[6- LC-MS, m/z; methyl-3-(propan-2-yl)-1H-
395 [M - tBu + H]+ indazol-1-yl]-1,2,4- oxadiazol-5-yl}piperidin-1-
yl)methyl]azetidine-1- carboxylate 314 Et F F tert-butyl
3-({4-[3-(3- LC-MS, m/z; ethyl-6,7-difluoro-1H- 525 [M + Na]+
indazol-1-yl)-1,2,4- oxadiazol-5-yl]piperidin-1-
yl}methyl)azetidine-1- carboxylate 315 .sup.iPr F F tert-butyl
3-[(4-{3-[6,7- LC-MS, m/z; difluoro-3-(propan-2-yl)- 539 [M + Na]+
1H-indazol-1-yl]-1,2,4- oxadiazol-5-yl}piperidin-1-
yl)methyl]azetidine-1- carboxylate
[0846] The compounds in the following table (i.e. Examples 316 to
319) were prepared in the same manner as in Example 028 except that
the 3-ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and
(S)-(-)-1-tert-butoxycarbonyl-2-pyrrolidinecarbaldehyde were
replaced with the corresponding starting compound and tert-butyl
4-formylpiperidine-1-carboxylate, respectively.
##STR00364##
[0847] Wherein HX is hydrochloric acid or trifluoroacetic acid.
TABLE-US-00050 TABLE 50 Ex. R.sup.3 R.sup.6 R.sup.7 Compound Name
LC-MS, m/z 316 .sup.iPr H H tert-butyl 4-[(4-{3-[3- LC-MS, m/z;
(propan-2-yl)-1H-indazol-1- 509 [M + H]+ yl]-1,2,4-oxadiazol-5-
yl}piperidin-1- yl)methyl]piperidine-1- carboxylate 317 .sup.iPr Me
H tert-butyl 4-[(4-{3-[6-methyl- LC-MS, m/z;
3-(propan-2-yl)-1H-indazol-1- 523 [M + H]+ yl]-1,2,4-oxadiazol-5-
yl}piperidin-1- yl)methyl]piperidine-1- carboxylate 318 Et F F
tert-butyl 4-({4-[3-(3-ethyl- LC-MS, m/z;
6,7-difluoro-1H-indazol-1-yl)- 531 [M + H]+ 1,2,4-oxadiazol-5-
yl]piperidin-1- yl}methyl)piperidine-1- carboxylate 319 .sup.iPr F
F tert-butyl 4-[(4-{3-[6,7- LC-MS, m/z;
difluoro-3-(propan-2-yl)-1H- 545 [M + H]+
indazol-1-yl]-1,2,4-oxadiazol- 5-yl}piperidin-1-
yl)methyl]piperidine-1- carboxylate
Example 320
Preparation of tert-butyl
4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-4-h-
ydroxy-1,4'-bipiperidine-1'-carboxylate
##STR00365##
[0849] The title compound was prepared in the same manner as in
Example 028 except that the
3-ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and
(S)-(-)-1-tert-butoxycarbonyl-2-pyrrolidinecarbaldehyde were
replaced with
4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl-
}piperidin-4-ol hydrochloride (Example 299) and tert-butyl
4-oxopiperidine-1-carboxylate, respectively.
[0850] LC-MS, m/z; 529 [M+H]+
[0851] The compounds in the following table (i.e. Examples 321 to
325) were prepared in the same manner as in Example 028 except that
the 3-ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and
(S)-(-)-1-tert-butoxycarbonyl-2-pyrrolidinecarbaldehyde were
replaced with the corresponding starting compound and aldehyde or
ketone, respectively.
##STR00366##
[0852] Wherein (R.sup.12-1) means each cyclic amino structure shown
in the following table, HX is hydrochloric acid or trifluoroacetic
acid, and the Boc group is attached to the nitrogen atom in the
cyclic amine of (R.sup.12-1).
TABLE-US-00051 TABLE 51 Ex. (R.sup.12-1) Compound Name
.sup.1H-NMR/LC-MS, m/z 321 ##STR00367## tert-butyl
2-[(4-{3-[7-fluoro-3- (propan-2-yl)-1H-indazol-1-yl]-
1,2,4-oxadiazol-5-yl}piperidin 1-yl)methyl]morphline-4- carboxylate
LC-MS, m/z; 529 [M + H]+ 322.sup.1) ##STR00368## tert-butyl
4-{3-[7-fluoro-3- (propan-2-yl)-1H-indazol-1-yl]-
1,2,4-oxadiazol-5-yl}-3'-methyl- 1,4'-bipiperidine-1'-carboxylate
LC-MS, m/z; 527 [M + H]+ 323.sup.1) ##STR00369## tert-butyl
3-(4-{3-[7-fluoro-3- (propan-2-yl)-1H-indazol-1-yl]-
1,2,4-oxadiazol-5-yl}piperidin- 1-yl)-8-azabicyclo[3.2.1]octane-
8-carboxylate LC-MS, m/z; 539 [M + H]+ 324.sup.1) ##STR00370##
tert-butyl 9-(4-{3-[7-fluoro-3- (propan-2-yl)-1H-indazol-1-yl]-
1,2,4-oxadiazol-5-yl}piperidin- 1-yl)-3-azabicyclo[3.3.1]nonane-
3-carboxylate LC-MS, m/z; 553 [M + H]+ 325.sup.1) ##STR00371##
tert-butyl 8-(4-{3-[7-fluoro-3- (propan-2-yl)-1H-indazol-1-yl]-
1,2,4-oxadiazol-5-yl}piperidin- 1-yl)-3-azabicyclo[3.2.1]octane-
3-carboxylate LC-MS, m/z; 539 [M + H]+ .sup.1)Titanium
tetraisopropoxide was added to the reaction system.
[0853] The compounds in the following table (i.e. Examples 326 to
329) were prepared in the same manner as in Example 028 except that
the 3-ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and
(S)-(-)-1-tert-butoxycarbonyl-2-pyrrolidinecarbaldehyde were
replaced with
7-fluoro-3-(propan-2-yl)-1-{5-[(3R)-pyrrolidin-3-ylmethyl]-1,2,4-oxa-
diazol-3-yl}-1H-indazole trifluoroacetate (Example 304) and
aldehyde or ketone, respectively.
##STR00372##
Wherein (R.sup.12-1) means each cyclic amino structure shown in the
following table, and the Boc group is attached to the nitrogen atom
in the cyclic amine of (R.sup.12-1).
TABLE-US-00052 TABLE 52 Ex. (R.sup.12-1) Compound Name
.sup.1H-NMR/LC-MS, m/z 326 ##STR00373## tert-butyl
4-[(3R)-3-({3-[7- fluoro-3-(propan-2-yl)-1H-
indazol-1-yl]-1,2,4-oxadiazol-5- yl}methyl)pyrrolidin-1-
yl]piperidine-1-carboxylate LC-MS, m/z; 513 [M + H]+ 327
##STR00374## tert-butyl (2S)-2-{[(3R)-3-({3-
[7-fluoro-3-(propan-2-yl)-1H- indazol-1-yl]-1,2,4-oxadiazol-5-
yl}methyl)pyrrolidin-1- yl]methyl}pyrrolidine-1- carboxylate LC-MS,
m/z; 513 [M + H]+ 328 ##STR00375## tert-butyl (2R)-2-{[(3R)-3-({3-
[7-fluoro-3-(propan-2-yl)-1H- indazol-1-yl]-1,2,4-oxadiazol-5-
yl}methyl)pyrrolidin-1- yl]methyl}pyrrolidine-1- carboxylate LC-MS,
m/z; 513 [M + H]+ 329 ##STR00376## tert-butyl 3-{[(3R)-3-({3-[7-
fluoro-3-(propan-2-yl)-1H- indazol-1-yl]-1,2,4-oxadiazol-5-
yl}methyl)pyrrolidin-1- yl]methyl}azetidine-1-carboxylate LC-MS,
m/z; 499 [M + H]+
[0854] The compounds in the following table (i.e. Examples 330 to
333) were prepared in the same manner as in Example 028 except that
the 3-ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and
(S)-(-)-1-tert-butoxycarbonyl-2-pyrrolidinecarbaldehyde were
replaced with
7-fluoro-3-(propan-2-yl)-1-{5-[(3S)-pyrrolidin-3-ylmethyl]-1,2,4-oxa-
diazol-3-yl}-1H-indazole trifluoroacetate (Example 305) and
aldehyde or ketone, respectively.
##STR00377##
Wherein (R.sup.12-1) means each cyclic amino structure shown in the
following table, and the Boc group is attached to the nitrogen atom
in the cyclic amine of (R.sup.12-1).
TABLE-US-00053 TABLE 53 .sup.1H-NMR/ LC-MS, Ex. (R.sup.12-1)
Compound Name m/z 330 ##STR00378## tert-butyl 4- [(3S)-3-({3-[7-
fluoro-3-(propan- 2-yl)-1H- indazol-1- yl]-1,2,4- oxadiazol-
5-yl}methyl) pyrrolidin- 1-yl]piperidine- 1-carboxylate LC-MS, m/z;
513 [M + H]+ 331 ##STR00379## tert-butyl (2S)- 2-{[(3S)-3-
({3-[7-fluoro- 3-(propan- 2-yl)-1H- indazol-1- yl]-1,2,4-
oxadiazol- 5-yl}methyl) pyrrolidin- 1-yl]methyl} pyrrolidine-
1-carboxylate LC-MS, m/z; 513 [M + H]+ 332 ##STR00380## tert-butyl
(2R)- 2-{[(3S)-3- ({3-[7-fluoro- 3-(propan- 2-yl)-1H- indazol-1-
yl]-1,2,4- oxadiazol- 5-yl}methyl) pyrrolidin- 1-yl]methyl}
pyrrolidine- 1-carboxylate LC-MS,m/z; 513 [M + H]+ 333 ##STR00381##
tert-butyl 3- {[(3S)-3-({3-[7- fluoro-3-(propan- 2-yl)-1H-
indazol-1-yl]- 1,2,4-oxadiazol- 5-yl}methyl) pyrrolidin-1-
yl]methyl} azetidine-1- carboxylate LC-MS, m/z; 499 [M + H]+
Example 334
Preparation of tert-butyl
4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-1,4-
'-bipiperidine-1'-carboxylate
##STR00382##
[0856] 1'-(Tert-butoxycarbonyl)-1,4'-bipiperidine-4-carboxylic acid
(120 g) and triethylamine (124 ml) were suspended in THF (1000 ml).
To the suspension was added dropwise isopropyl chlorocarbonate
(47.2 g) at ice temperature, and the mixture was stirred at
40.degree. C. for 1.5 hours. To the reaction mixture was added
7-fluoro-N'-hydroxy-3-(propan-2-yl)-1H-indazole-1-carboximidamide
(70.0 g), and the mixture was stirred at 40.degree. C. for 8 hours
and further stirred at room temperature for 15 hours. To the
reaction mixture was added saturated sodium bicarbonate (500 ml),
and the mixture was stirred at room temperature for 30 minutes. To
the mixture was further added saturated sodium bicarbonate (400
ml), and the resultant mixture was extracted with ethyl acetate
(1500 ml). The organic layer was washed with saturated sodium
bicarbonate (900 ml) and brine (900 ml), dried over anhydrous
sodium sulfate, and concentrated under reduced pressure. The
residue (149 g) was dissolved in toluene (1490 ml), 25%
tetramethylammonium hydroxide aqueous solution (10.1 ml) was added
thereto, and the mixture was stirred at 60.degree. C. for 30
minutes. Then the reaction mixture was washed with water (1500 ml)
and brine (1500 ml). The organic layer was dried over anhydrous
sodium sulfate and concentrated under reduced pressure to give a
quantitative amount of the title compound.
[0857] LC-MS, m/z; 513 [M+H]+
[0858] The compounds in the following table (i.e. Examples 335 to
341) were prepared in the same manner as in Example 334 except that
the
7-fluoro-N'-hydroxy-3-(propan-2-yl)-1H-indazole-1-carboximidamide
was replaced with the corresponding starting compound.
##STR00383##
TABLE-US-00054 TABLE 54 .sup.1H-NMR/ Ex. R.sup.3 R.sup.4 R.sup.6
R.sup.7 Compound Name LC-MS, m/z 335.sup.1) ##STR00384## H H F
tert-butyl 4-{3- [7-fluoro-3-(2- hydroxypropan-2- yl)-1H-indazol-1-
yl]-1,2,4- oxadiazol-5-yl}- 1,4'-bipiperidine- 1'-carboxylate
LC-MS, m/z; 529 [M + H]+ 336.sup.1) .sup.iPr H MeO F tert-butyl
4-{3- [7-fluoro-6- methoxy-3-(propan- 2-yl)-1H-indazol-
1-yl]-1,2,4- oxadiazol-5-yl}- 1,4'-bipiperidine- 1'-carboxylate
LC-MS, m/z; 543 [M + H]+ 337.sup.1) .sup.iPr MeO H F tert-butyl
4-{3- [7-fluoro-4- methoxy-3-(propan- 2-yl)-1H-indazol-
1-yl]-1,2,4- oxadiazol-5-yl}- 1,4'-bipiperidine- 1'-carboxylate
LC-MS, m/z; 543 [M + H]+ 338 ##STR00385## H H F tert-butyl 4-{3-
[7-fluoro-3-(prop- 1-en-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}-1,4'- bipiperidine-1'- carboxylate TLC Rf = 0.25 (hexane/ EtOAc
= 3/1) .sup.1)The cyclization reaction was carried out in the same
manner as in Reference Example 33 except that the
tetramethylammonium hydroxide aqueous solution was replaced with 1M
tetra-butylammonium fluoride/THF.
TABLE-US-00055 TABLE 55 Compound .sup.1H-NMR/ Ex. R.sup.3 R.sup.4
R.sup.6 R.sup.7 Name LC-MS, m/z 339 ##STR00386## H H H tert-butyl
4- [3-(3-tert- butyl-1H- indazol-1-yl)- 1,2,4-oxadiazol- 5-yl]-
1,4'- bipiperidine-1'- carboxylate LC-MS, m/z; 509 [M + H]+ 340
##STR00387## H H F tert-butyl 4- {3-[3- (butan-2-yl)- 7-fluoro-
1H-indazol- 1-yl]-1,2,4- oxadiazol- 5-yl}-1,4'- bipiperidine-1'-
carboxylate LC-MS, m/z; 527 [M + H]+ 341 I H H F tert-butyl 4-
[3-(7- fluoro-3- iodo-1H- indazol-1- yl)-1,2,4- oxadiazol-
5-yl]-1,4'- bipiperidine-1'- carboxylate LC-MS, m/z; 597 [M +
H]+
[0859] The compounds in the following table (i.e. Examples 342 to
344) were prepared in the same manner as in Example 334 except that
the 1'-(tert-butoxycarbonyl)-1,4'-bipiperidine-4-carboxylic acid
was replaced with the corresponding carboxylic acid.
##STR00388##
Wherein (R.sup.12-1) means each cyclic amino structure shown in the
following table, and the Boc group is attached to the nitrogen atom
in the cyclic amine of (R.sup.12-1).
TABLE-US-00056 TABLE 56 Compound .sup.1H-NMR/ Ex. R.sup.3
(R.sup.12-1) Name LC-MS, m/z 342 .sup.iPr ##STR00389## tert-butyl
4- {3-[7-fluoro-3- (propan-2-yl)- 1H-indazol-1- yl]-1,2,4-
oxadiazol-5-yl}- 3',3'-dimethyl-1,4'- bipiperidine- 1'-carboxylate
No data 343 .sup.iPr ##STR00390## tert-butyl 4- {3-[7-fluoro-3-
(propan-2-yl)- 1H-indazol-1- yl]-1,2,4- oxadiazol-5-yl}-
4'-methyl-1,4'- bipiperidine- 1'-carboxylate LC-MS, m/z; 527 [M +
H]+ 344 Et tert-butyl 4-[3- (3-ethyl-7- fluoro-1H- indazol-1-yl)-
1,2,4-oxadiazol- 5-yl]-4'- methyl-1,4'- bipiperidine-1'-
carboxylate LC-MS, m/z; 513 [M + H]+
Example 345
Preparation of tert-butyl
4-[3-(3-cyclopropyl-7-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-1,4'--
bipiperidine-1'-carboxylate
##STR00391##
[0861] Under nitrogen atmosphere, tert-butyl
4-[3-(7-fluoro-3-iodo-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-1,4'-bipiper-
idine-1'-carboxylate (100 mg), cyclopropylboronic acid (29 mg),
potassium phosphate (107 mg),
1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (12 mg),
water (0.3 ml) and toluene (2 ml) were mixed, and the mixture was
stirred at 110.degree. C. for 2.5 hours. The reaction solution was
purified by amino column chromatography (eluate: hexane/ethyl
acetate=100/0-0/100) to give the title compound (49 mg).
[0862] LC-MS, m/z; 511 [M+H]+
Example 346
Preparation of tert-butyl
4-[3-(7-fluoro-3-methyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-1,4'-bipip-
eridine-1'-carboxylate
##STR00392##
[0864] Under nitrogen atmosphere, tert-butyl
4-[3-(7-fluoro-3-iodo-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-1,4'-bipiper-
idine-1'-carboxylate (150 mg), 2 mol/L methyl zinc
chloride/tetrahydrofuran (0.4 ml),
bis(tri-tert-butylphosphine)palladium (26 mg) and tetrahydrofuran
(1 ml) were mixed, and the mixture was stirred at room temperature
for 3 hours. The reaction solution was purified by amino column
chromatography (eluate: hexane/ethyl acetate=100/0-0/100) to give
the title compound (64 mg).
[0865] LC-MS, m/z; 485 [M+H]+
[0866] The compounds in the following table (i.e. Examples 347 to
349) were prepared in the same manner as in Example 346 except that
the methyl zinc chloride was replaced with the corresponding zinc
reagent.
TABLE-US-00057 TABLE 57 .sup.1H-NMR/ Ex. R.sup.3 Compound Name
LC-MS, m/z 347 .sup.nPr tert-butyl 4-[3-(7-fluoro-3-
propyl-1H-indazol-1-yl)-1,2,4- oxadiazol-5-yl]-1,4'-
bipiperidine-1'-carboxylate LC-MS, m/z; 513 [M + H]+ 348 .sup.iBu
tert-butyl 4-{3-[7-fluoro-3-(2- methylpropyl)-1H-indazol-1-yl]-
1,2,4-oxadiazol-5-yl}-1,4'- bipiperidine-1'-carboxylate LC-MS, m/z;
527 [M + H]+ 349 ##STR00393## tert-butyl 4-[3-(3-cyclobutyl-7-
fluoro-1H-indazol-1-yl)-1,2,4- oxadiazol-5-yl]-1,4'-
bipiperidine-1'-carboxylate LC-MS, m/z; 525 [M + H]+
[0867] The compounds in the following table (i.e. Examples 350 to
351) were prepared in the same manner as in Example 035 except that
the 3-ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and tert-butyl
(3R)-3-(iodomethyl)pyrrolidine-1-carboxylate were replaced with
7-fluoro-3-(propan-2-yl)-1-{5-[(3R)-pyrrolidin-3-ylmethyl]-1,2,4-oxadiazo-
l-3-yl}-1H-indazole trifluoroacetate (Example 304) and tert-butyl
(3R)-3-(iodomethyl)pyrrolidine-1-carboxylate or tert-butyl
(3S)-3-(iodomethyl)pyrrolidine-1-carboxylate, respectively.
##STR00394##
Wherein (R.sup.12-1) means each cyclic amino structure shown in the
following table, and the Boc group is attached to the nitrogen atom
in the cyclic amine of (R.sup.12-1).
TABLE-US-00058 TABLE 58 Compound .sup.1H-NMR/ Ex. (R.sup.12-1) Name
LC-MS, m/z 350 ##STR00395## tert-butyl (3S)- 3-{[(3R)-3-({3-
[7-fluoro-3- (propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-
5-yl}methyl) pyrrolidin-1- yl]methyl} pyrrolidine-1- carboxylate
LC-MS, m/z; 513 [M + H]+ 351 ##STR00396## tert-butyl (3R)-
3-{[(3R)-3-({3- [7-fluoro-3- (propan-2-yl)-1H- indazol-1-yl]-
1,2,4-oxadiazol- 5-yl}methyl) pyrrolidin-1- yl]methyl}
pyrrolidine-1- carboxylate LC-MS, m/z; 513 [M + H]+
[0868] The compounds in the following table (i.e. Examples 352 to
353) were prepared in the same manner as in Example 035 except that
the 3-ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and tert-butyl
(3R)-3-(iodomethyl)pyrrolidine-1-carboxylate were replaced with
7-fluoro-3-(propan-2-yl)-1-{5-[(3S)-pyrrolidin-3-ylmethyl]-1,2,4-oxadiazo-
l-3-yl}-1H-indazole trifluoroacetate and tert-butyl
(3R)-3-(iodomethyl)pyrrolidine-1-carboxylate or tert-butyl
(3S)-3-(iodomethyl)pyrrolidine-1-carboxylate, respectively.
##STR00397##
Wherein (R.sup.12-1) means each cyclic amino structure shown in the
following table, and the Boc group is attached to the nitrogen atom
in the cyclic amine of (R.sup.12-1).
TABLE-US-00059 TABLE 59 .sup.1H-NMR/ Ex. (R.sup.12-1) Compound Name
LC-MS, m/z 352 ##STR00398## tert-butyl (3S)-3-{[(3S)-
3-({3-[7-fluoro-3-(propan- 2-yl)-1H-indazol-1-yl]-
1,2,4-oxadiazol-5- yl}methyl)pyrrolidin-1- yl]methyl}pyrrolidine-1-
carboxylate LC-MS, m/z; 513 [M + H]+ 353 ##STR00399## tert-butyl
(3R)-3-{[(3S)- 3-({3-[7-fluoro-3-(propan- 2-yl)-1H-indazol-1-yl]-
1,2,4-oxadiazol-5- yl}methyl)pyrrolidin-1- yl]methyl}pyrrolidine-1-
carboxylate LC-MS, m/z; 513 [M + H]+
[0869] The compounds in the following table (i.e. Examples 354 to
367) were prepared in the same manner as in Example 053 or Example
054 except that the tert-butyl
4-[(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-
piperidin-1-yl)methyl]piperidine-1-carboxylate of Example 053 or
the tert-butyl
3-[(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-
piperidin-1-yl)methyl]azetidine-1-carboxylate of Example 054 was
replaced with the corresponding starting compound.
##STR00400##
herein HX is hydrochloric acid or trifluoroacetic acid.
TABLE-US-00060 TABLE 60 .sup.1H-NMR/ Ex. R.sup.3 R.sup.4 R.sup.6
R.sup.7 Compound Name LC-MS, m/z 354 .sup.iPr H H H
4-{3-[3-(propan-2- yl)-1H-indazol-1- yl]-1,2,4-oxadiazol-
5-yl}-1,4'- bipiperidine dihydrochloride LC-MS, m/z; 395 [M + H]+
355 ##STR00401## H H H 4-[3-(3-tert-butyl- 1H-indazol-1-yl)-
1,2,4-oxadiazol-5- yl]-1,4'- bipiperidine bis(trifluoroacetate)
LC-MS, m/z; 409 [M + H]+ 356 .sup.iPr H Me H 4-{3-[6-methyl-3-
(propan-2-yl)-1H- indazol-1-yl]-1,2,4- oxadiazol-5-yl}-
1,4'-bipiperidine dihydrochloride LC-MS, m/z; 409 [M + H]+ 357 Et H
F F 4-[3-(3-ethyl-6,7- difluoro-1H-indazol- 1-yl)-1,2,4-
oxadiazol-5-yl]- 1,4'-bipiperidine dihydrochloride LC-MS, m/z; 417
[M + H]+ 358 .sup.iPr H F F 4-{3-[6,7-difluoro- 3-(propan-2-yl)-1H-
indazol-1-yl]-1,2,4- oxadiazol-5-yl}- 1,4'-bipiperidine
dihydrochloride LC-MS,m/z; 431 [M + H]+ 359 .sup.iPr H MeO F
4-{3-[7-fluoro-6- methoxy-3-(propan-2- yl)-1H-indazol-1-
yl]-1,2,4-oxadiazol- 5-yl}-1,4'- bipiperidine bis(trifluoroacetate)
LC-MS, m/z; 443 [M + H]+ 360 .sup.iPr MeO H F 4-{3-[7-fluoro-4-
methoxy-3-(propan-2- yl)-1H-indazol-1- yl]-1,2,4-oxadiazol-
5-yl}-1,4'- bipiperidine bis(trifluoroacetate) LC-MS, m/z; 443 [M +
H]+ 361 ##STR00402## H H F 4-{3-[7-fluoro-3- (prop-1-en-2-yl)-1H-
indazol-1-yl]-1,2,4- oxadiazol-5-yl}- 1,4'-bipiperidine
bis(trifluoroacetate) LC-MS, m/z; 411 [M + H]+ 362 ##STR00403## H H
F 4-{3-[3-(butan-2- yl)-7-fluoro-1H- indazol-1-yl]-1,2,4-
oxadiazol-5-yl}- 1,4'-bipiperidine dihydrochloride LC-MS, m/z; 427
[M + H]+ 363 ##STR00404## H H F 4-[3-(3-cyclopropyl-
7-fluoro-1H-indazol- 1-yl)-1,2,4- oxadiazol-5-yl]-
1,4'-bipiperidine dihydrochloride LC-MS, m/z; 411 [M + H]+ 364
.sup.nPr H H F 4-[3-(7-fluoro-3- propyl-1H-indazol-1-
yl)-1,2,4-oxadiazol- 5-yl]-1,4'- bipiperidine dihydrochloride
LC-MS, m/z; 413 [M + H]+ 365 Me H H F 4-[3-(7-fluoro-3-
methyl-1H-indazol-1- yl)-1,2,4-oxadiazol- 5-yl]-1,4'- bipiperidine
dihydrochloride LC-MS, m/z; 385 [M + H]+ 366 .sup.iBu H H F
4-{3-[7-fluoro-3-(2- methylpropyl)-1H- indazol-1-yl]-1,2,4-
oxadiazol-5-yl}- 1,4'-bipiperidine dihydrochloride LC-MS, m/z; 427
[M + H]+ 367 ##STR00405## H H F 4-[3-(3-cyclobutyl-
7-fluoro-1H-indazol- 1-yl)-1,2,4- oxadiazol-5-yl]-
1,4'-bipiperidine dihydrochloride LC-MS, m/z; 425 [M + H]+
[0870] The compounds in the following table (i.e. Examples 368 to
383) were prepared in the same manner as in Example 053 or Example
054 except that the tert-butyl
4-[(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-
piperidin-1-yl)methyl]piperidine-1-carboxylate of Example 053 or
the tert-butyl
3-[(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-
piperidin-1-yl)methyl]azetidine-1-carboxylate of Example 054 was
replaced with the corresponding starting compound.
##STR00406##
Wherein (R.sup.12-1) means each cyclic amino structure shown in the
following table, the Hoc group is attached to the nitrogen atom in
the cyclic amine of (R.sup.12-1), and HX is hydrochloric acid or
trifluoroacetic acid.
TABLE-US-00061 TABLE 61 Ex. R.sup.3 R.sup.6 R.sup.7 (R.sup.12-1)
Compound Name LC-MS, m/z 368 .sup.iPr H H ##STR00407## 1-{5-[1-
(azetidin-3- ylmethyl)piperidin- 4-yl]-1,2,4- oxadiazol-3-yl}-
3-(propan-2-yl)- 1H-indazole bis(trifluoroacetate) LC-MS, m/z; 381
[M + H]+ 369 .sup.iPr Me H 1-{5-[1- (azetidin-3-
ylmethyl)piperidin- 4-yl]-1,2,4- oxadiazol-3-yl}- 6-methyl-3-
(propan-2-yl)- 1H-indazole bis(trifluoroacetate) LC-MS, m/z; 395 [M
+ H]+ 370 Et F F ##STR00408## 1-{5-[1- (azetidin-3-
ylmethyl)piperidin- 4-yl]-1,2,4- oxadiazol-3-yl}- 3-ethyl-6,7-
difluoro-1H- indazole bis(trifluoroacetate) No data 371 .sup.iPr F
F 1-{5-[1- (azetidin-3- ylmethyl)piperidin- 4-yl]-1,2,4-
oxadiazol-3-yl}- 6,7-difluoro-3- (propan-2-yl)- 1H-indazole
bis(trifluoroacetate) No data 372 .sup.iPr H H ##STR00409##
1-{5-[1- (piperidin-4- ylmethyl)piperidin- 4-yl]-1,2,4-
oxadiazol-3-yl}- 3-(propan-2-yl)- 1H-indazole bis(trifluoroacetate)
LC-MS, m/z; 409 [M + H]+ 373 .sup.iPr Me H 6-methyl-1-{5-
[1-(piperidin-4- ylmethyl)piperidin- 4-yl]-1,2,4- oxadiazol-3-yl}-
3-(propan-2-yl)- 1H-indazole bis(trifluoroacetate) LC-MS, m/z; 423
[M + H]+ 374 Et F F 3-ethyl-6,7- difluoro-1-{5- [1-(piperidin-4-
ylmethyl)piperidin- 4-yl]-1,2,4- oxadiazol-3-yl}- 1H-indazole
dihydrochloride LC-MS, m/z; 431 [M + H]+ 375 .sup.iPr F F
6,7-difluoro-1- {5-[1- (piperidin-4- ylmethyl)piperidin-
4-yl]-1,2,4- oxadiazol-3-yl}- 3-(propan-2-yl)- 1H-indazole
dihydrochloride LC-MS, m/z; 445 [M + H]+ 376 .sup.iPr H F
##STR00410## 7-fluoro-1-{5- [1-(morpholin-2- ylmethyl)piperidin-
4-yl]-1,2,4- oxadiazol-3-yl}- 3-(propan-2-yl)- 1H-indazole
dihydrochloride No data 377 .sup.iPr H F ##STR00411##
4-{3-[7-fluoro- 3-(propan-2-yl)- 1H-indazol-1- yl]-1,2,4-
oxadiazol-5-yl}- 3'-methyl-1,4'- bipiperidine bis(trifluoroacetate)
LC-MS, m/z; 427 [M + H]+ 378 .sup.iPr H F ##STR00412## 1-{5-[1-(8-
azabicyclo[3.2.1] oct-3-yl)piperidin-4- yl]-1,2,4- oxadiazol-3-yl}-
7-fluoro-3- (propan-2-yl)- 1H-indazole bis(trifluoroacetate) LC-MS,
m/z; 439 [M + H]+ 379 .sup.iPr H F ##STR00413## 1-{5-[1-(3-
azabicyclo[3.3.1] non-9- yl)piperidin-4- yl]-1,2,4-
oxadiazol-3-yl}- 7-fluoro-3- (propan-2-yl)- 1H-indazole
bis(trifluoroacetate) LC-MS, m/z; 453 [M + H]+ 380 .sup.iPr H F
##STR00414## 1-{5-[1-(3- azabicyclo[3.2.1] oct-8- yl)piperidin-4-
yl]-1,2,4- oxadiazol-3-yl}- 7-fluoro-3- (propan-2-yl)- 1H-indazole
bis(trifluoroacetate) LC-MS, m/z; 439 [M + H]+ 381 .sup.iPr H F
##STR00415## 4-{3-[7-fluoro- 3-(propan-2-yl)- 1H-indazol-1-
yl]-1,2,4- oxadiazol-5-yl}- 3',3'-dimethyl- 1,4'- bipiperidine
bis(trifluoroacetate) No data 382 .sup.iPr H F ##STR00416##
4-{3-[7-fluoro- 3-(propan-2-yl)- 1H-indazol-1- yl]-1,2,4-
oxadiazol-5-yl}- 4'-methyl-1,4'- bipiperidine bis(trifluoroacetate)
LC-MS, m/z; 427 [M + H]+ 383 Et H F 4-[3-(3-ethyl-7- fluoro-1H-
indazol-1-yl)- 1,2,4-oxadiazol- 5-yl]-4'-methyl- 1,4'- bipiperidine
bis(trifluoroacetate) LC-MS, m/z; 413 [M + H]+
Example 384
Preparation of
4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-1,4-
'-bipiperidin-4-ol dihydrochloride
##STR00417##
[0872] The title compound was prepared in the same manner as in
Example 053 except that the tert-butyl
4-[(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-
piperidin-1-yl)methyl]piperidine-1-carboxylate was replaced with
tert-butyl
4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-4-h-
ydroxy-1,4'-bipiperidine-1'-carboxylate (Example 320).
[0873] LC-MS, m/z; 429 [M+H]+
[0874] The compounds in the following table (i.e. Examples 385 to
388) were prepared in the same manner as in Example 054 except that
the tert-butyl
3-[(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-
piperidin-1-yl)methyl]azetidine-1-carboxylate was replaced with the
corresponding starting compound.
##STR00418##
Wherein (R.sup.12-1) means each cyclic amino structure shown in the
following table, and the Boc group is attached to the nitrogen atom
in the cyclic amine of (R.sup.12-1).
TABLE-US-00062 TABLE 62 Ex. (R.sup.12-1) Compound Name LC-MS, m/z
385 ##STR00419## 7-fluoro-1-(5-{[(3R)-1-
(piperidin-4-yl)pyrrolidin- 3-yl]methyl}-1,2,4-oxa-
diazol-3-yl)-3-(propan- 2-yl)-1H-indazole bis(trifluoroacetate)
LC-MS, m/z; 413 [M + H]+ 386 ##STR00420## 7-fluoro-3-(propan-2-yl)-
1-[5-({(3R)-1-[(2S)- pyrrolidin-2-ylmethyl]
pyrrolidin-3-yl}methyl)- 1,2,4-oxadiazol-3-yl]- 1H-indazole
bis(trifluoro- acetate) LC-MS, m/z; 413 [M + H]+ 387 ##STR00421##
7-fluoro-3-(propan-2-yl)- 1-[5-({(3R)-1-[(2R)-
pyrrolidin-2-ylmethyl] pyrrolidin-3-yl}methyl)-
1,2,4-oxadiazol-3-yl]- 1H-indazole bis(trifluoro- acetate) LC-MS,
m/z; 413 [M + H]+ 388 ##STR00422## 1-(5-{[(3R)-1-(azetidin-
3-ylmethyl)pyrrolidin-3- yl]methyl}-1,2,4-oxa-
diazol-3-yl)-7-fluoro-3- (propan-2-yl)-1H- indazole bis(trifluoro-
acetate) LC-MS, m/z; 399 [M + H]+
[0875] The compounds in the following table (i.e. Examples 389 to
392) were prepared in the same manner as in Example 054 except that
the tert-butyl
3-[(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-
piperidin-1-yl)methyl]azetidine-1-carboxylate was replaced with the
corresponding starting compound.
##STR00423##
[0876] Wherein (R.sup.12-1) means each cyclic amino structure shown
in the following table, and the Boc group is attached to the
nitrogen atom in the cyclic amine of (R.sup.12-1).
TABLE-US-00063 TABLE 63 Ex. (R.sup.12-1) Compound Name LC-MS, m/z
389 ##STR00424## 7-fluoro-1-(5-{[(3S)-1-
(piperidin-4-yl)pyrrolidin- 3-yl]methyl}-1,2,4-
oxadiazol-3-yl)-3-(propan- 2-yl)-1H-indazole bis(trifluoroacetate)
LC-MS, m/z; 413 [M + H]+ 390 ##STR00425##
7-fluoro-3-(propan-2-yl)-1- [5-({(3S)-1-[(2S)- pyrrolidin-2-
ylmethyl]pyrrolidin-3- yl}methyl)-1,2,4-oxadiazol-
3-yl]-1H-indazole bis(trifluoroacetate) LC-MS, m/z; 413 [M + H]+
391 ##STR00426## 7-fluoro-3-(propan-2-yl)-1- [5-({(3S)-1-[(2R)-
pyrrolidin-2- ylmethyl]pyrrolidin-3- yl}methyl)-1,2,4-oxadiazol-
3-yl]-1H-indazole bis(trifluoroacetate) LC-MS, m/z; 413 [M + H]+
392 ##STR00427## 1-(5-{[(3S)-1-(azetidin-3- ylmethyl)pyrrolidin-3-
yl]methyl}-1,2,4-oxadiazol- 3-yl)-7-fluoro-3-(propan-2-
yl)-1H-indazole bis(trifluoroacetate) LC-MS, m/z; 399 [M + H]+
Example 393
Preparation of
1-(4-{3-[7-fluoro-3-(2-hydroxypropan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiaz-
ol-5-yl}-1,4'-bipiperidin-1'-yl)-2-hydroxyethanone
##STR00428##
[0878] (1) Tert-butyl
4-{3-[7-fluoro-3-(2-hydroxypropan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol--
5-yl}-1,4'-bipiperidine-1'-carboxylate (2.57 g) was dissolved in
acetonitrile (125 ml). To the solution were added sodium iodide
(2.33 g) and trimethylsilyl chloride (1.86 ml) under nitrogen
atmosphere, and the mixture was stirred at room temperature for 2
hours. The reaction solution was cooled to -10.degree. C. To the
resultant were added sodium bicarbonate (4.09 g), water (75 ml),
dichloromethane (115 ml) and acetoxyacetyl chloride (784 .mu.l),
and the mixture was stirred for 15 minutes. The organic layer was
separated, washed with brine, dried, and the solvent was removed
out. The residue was purified by silica-gel chromatography (column;
Hi-Flash.TM., developing solvent: chloroform/methanol=10:1) to give
2-(4-{3-[7-fluoro-3-(2-hydroxypropan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiaz-
ol-5-yl}-1,4'-bipiperidin-1'-yl)-2-oxoethyl acetate (2.24 g).
[0879] (2)
2-(4-{3-[7-Fluoro-3-(2-hydroxypropan-2-yl)-1H-indazol-1-yl]-1,2-
,4-oxadiazol-5-yl}-1,4'-bipiperidin-1'-yl)-2-oxoethyl acetate (2.24
g) was dissolved in methanol (50 ml). To the solution was added
methylamine (in 40% methanol, 1.72 ml), and the mixture was stirred
at room temperature for 3 hours. The solvent was removed under
reduced pressure, and the residue was recrystallized from
2-propanol (22 ml) to give the title compound (1.64 g) as a white
crystal.
[0880] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.20-1.48 (2H, m),
1.59-1.87 (11H, m), 2.10 (2H, d, J=10.5 Hz), 2.34 (2H, t, J=10.2
Hz), 2.49-2.67 (2H, m), 2.84-3.00 (3H, m), 3.09-3.22 (1H, m), 3.70
(1H, d, J=12.9 Hz), 4.07 (2H, t, J=6.1 Hz), 4.33-4.52 (2H, m),
7.32-7.51 (2H, m), 8.02 (1H, d, J=8.0 Hz).
[0881] LC-MS, m/z; 487 [M+H]+
Example 394
Preparation of
7-fluoro-1-{5-[3-(piperidin-1-yl)propyl]-1,2,4-oxadiazol-3-yl}-3-(propan--
2-yl)-1H-indazole
##STR00429##
[0883] The title compound was prepared in the same manner as in
Reference Example 044 except that the
N'-hydroxy-3-(propan-2-yl)-1H-indazole-1-carboximidamide and
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid were replaced
with
7-fluoro-N'-hydroxy-3-(propan-2-yl)-1H-indazole-1-carboximidamide
and 4-(piperidin-1-yl)butanoic acid, respectively.
[0884] LC-MS, m/z; 372 [M+H]+
[0885] The compounds in the following table (i.e. Examples 395 to
400) were prepared in the same manner as in Example 097 except that
the
3-ethyl-6-fluoro-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and ethyl iodide were replaced with
7-fluoro-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-3-(propan-2-yl)-1H-i-
ndazole hydrochloride and R--X (which is an alkylating agent),
respectively.
##STR00430##
Each free form of the compounds in the following table was obtained
by omitting the conversion step into hydrochloride in Example
097.
TABLE-US-00064 TABLE 64 Ex. R Compound Name LC-MS, m/z 395
##STR00431## 7-fluoro-1-{5-[1-(3- phenoxypropyl)piperidin-4-yl]-
1,2,4-oxadiazol-3-yl}-3-(propan-2- yl)-1H-indazole LC-MS, m/z; 464
[M + H]+ 396 ##STR00432## 3-(4-{3-[7-fluoro-3-(propan-2-yl)-
1H-indazol-1-yl]-1,2,4-oxadiazol- 5-yl}piperidin-1-yl)-1-
phenylpropan-1-one LC-MS, m/z; 462 [M + H]+ 397 ##STR00433## methyl
4-(4-{3-[7-fluoro-3- (propan-2-yl)-1H-indazol-1-yl]-
1,2,4-oxadiazol-5-yl}piperidin-1- yl)butanoate LC-MS, m/z; 430 [M +
H]+ 398 ##STR00434## 3-(4-{3-[7-fluoro-3-(propan-2-yl)-
1H-indazol-1-yl]-1,2,4-oxadiazol- 5-yl}piperidin-1-yl)-N-
phenylpropanamide LC-MS, m/z; 477 [M + H]+ 399 ##STR00435##
7-fluoro-3-(propan-2-yl)-1-(5-{1- [2-(pyridin-3-yl)ethyl]piperidin-
4-yl}-1,2,4-oxadiazol-3-yl)-1H- indazole LC-MS, m/z; 435 [M + H]+
400 ##STR00436## tert-butyl 2-(4-{3-[7-fluoro-3-
(propan-2-yl)-1H-indazol-1-yl]- 1,2,4-oxadiazol-5-yl}piperidin-1-
yl)-2-methylpropanoate LC-MS, m/z; 472 [M + H]+
Example 401
Preparation of
2-(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}p-
iperidin-1-yl)-2-methylpropanoic acid hydrochloride
##STR00437##
[0887] A solution of tert-butyl
2-(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}p-
iperidin-1-yl)-2-methylpropanoate (280 mg, 0.59 mmol) in 30 mL of 4
N HCl-dioxane was stirred at 60.degree. C. for 2 hours. The solvent
was removed in vacuo to give the crude, which was purified with
preparative HPLC to give the pure product (220 mg, 89.1%) as a
white solid as HCl salt.
[0888] LC-MS, m/z; 416 [M+H]+
Example 402
Preparation of
2-(4-{3-[7-fluoro-3-(propan-2-yl)-1-indazol-1-yl]-1,2,4-oxadiazol-5-yl}pi-
peridin-1-yl)-2-methylpropan-1-ol
##STR00438##
[0890] To a solution of
2-(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}p-
iperidin-1-yl)-2-methylpropanoic acid hydrochloride (110 mg, 0.24
mmol) and triethylamine (0.07 mL, 0.48 mmol) in 5 mL of THF was
added isobutyl chloroformate (0.03 mL, 0.26 mmol). The mixture was
stirred at room temperature for 90 minutes. The white precipitation
was filtered and to the filtrate was added dropwise a solution of
sodium borohydride (46 mg, 1.2 mmol) in water (5 mL). The mixture
was washed with aq. saturated NaHCO.sub.3 (300 mL) and the organic
layer was washed with brine, dried over Na.sub.2SO.sub.4 and
evaporated in vacuo, which was purified with preparative HPLC to
give the pure product (40.3 mg, 40.3%) as a light-yellow solid as
free base.
[0891] LC-MS, m/z; 402 [M+H]+
[0892] The compounds in the following table (i.e. Examples 403 to
406) were prepared in the same manner as in Example 334 or the
tetramethylammonium hydroxide aqueous solution was replaced with 1M
tetrabutylammonium fluoride/THF solution, provided that that the
7-fluoro-N'-hydroxy-3-(propan-2-yl)-1H-indazole-1-carboximidamide
and 1'-(tert-butoxycarbonyl)-1,4'-bipiperidine-4-carboxylic acid of
Example 334 were replaced with the corresponding starting compound
and 1'-acetyl-1,4'-bipiperidine-4-carboxylic acid,
respectively.
##STR00439##
TABLE-US-00065 TABLE 65 .sup.1H-NMR/ Ex. R.sup.3 R.sup.4 R.sup.6
Compound Name LC-MS, m/z 403 ##STR00440## H H 1-(4-{3-[7-fluoro-
3-(2-hydroxypro- pan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-
5-yl}-1,4'-bi- piperidin-1'- yl)ethanone LC-MS, m/z; 471 [M + H]+
404 .sup.iPr H MeO 1-(4-{3-[7-fluoro- 6-methoxy-3- (propan-2-yl)-
1H-indazol-1-yl]- 1,2,4-oxadiazol- 5-yl}-1,4'-bi- piperidin-1'-yl)
ethanone LC-MS, m/z; 485 [M + H]+ 405 .sup.iPr MeO H 1-(4-{3-[7-
fluoro-4-methoxy- 3-(propan-2-yl)- 1H-indazol-1- yl]-1,2,4-
oxadiazol-5-yl}- 1,4'-bipiperidin- 1'-yl)ethanone LC-MS, m/z; 485
[M + H]+ 406 ##STR00441## H H 1-(4-{3-[7- fluoro-3-(trifluoro-
methyl)-1H- indazol-1-yl]- 1,2,4-oxadiazol- 5-yl}-1,4'-bipiper-
idin-1'-yl)ethanone LC-MS, m/z; 481 [M + H]+
[0893] The compounds in the following table (i.e. Examples 407 to
414) were prepared in the same manner as in Example 028 except that
the 3-ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and
(S)-(-)-1-tert-butoxycarbonyl-2-pyrrolidinecarbaldehyde were
replaced with the corresponding starting compound and
1-acetylpiperidin-4-one, respectively.
##STR00442##
Wherein HX is hydrochloric acid or trifluoroacetic acid.
TABLE-US-00066 TABLE 66 .sup.1H-NMR/ Ex. R.sup.4 R.sup.5 R.sup.6
R.sup.7 Compound Name LC-MS, m/z 407.sup.1) Cl H H H
1-(4-{3-[4-chloro- LC-MS, m/z; 3-(propan-2-yl)- 493 [M + Na]+
1H-indazol-1-yl]- 1,2,4-oxadiazol-5- yl}-1,4'- bipiperidin-1'-
yl)ethanone 408.sup.1) Me H H H 1-(4-{3-[4-methyl- LC-MS, m/z;
3-(propan-2-yl)- 473 [M + Na]+ 1H-indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}-1,4'- bipiperidin-1'- yl)ethanone 409.sup.1) H Cl H H
1-(4-{3-[5-chloro- LC-MS, m/z; 3-(propan-2-yl)- 493 [M + Na]+
1H-indazol-1-yl]- 1,2,4-oxadiazol-5- yl}-1,4'- bipiperidin-1'-
yl)ethanone 410.sup.1) H Me H H 1-(4-{3-[5-methyl- LC-MS, m/z;
3-(propan-2-yl)- 473 [M + Na]+ 1H-indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}-1,4'- bipiperidin-1'- yl)ethanone 411.sup.1) H MeO H H
1-(4-{3-[5- LC-MS, m/z; methoxy-3-(propan- 489 [M + Na]+
2-yl)-1H-indazol- 1-yl]-1,2,4- oxadiazol-5-yl}- 1,4'-bipiperidin-
1'-yl)ethanone 412.sup.1) H H Cl H 1-(4-{3-[6-chloro- LC-MS, m/z;
3-(propan-2-yl)- 493 [M + Na]+ 1H-indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}-1,4'- bipiperidin-1'- yl)ethanone 413.sup.1) H H H Me
1-(4-{3-[7-methyl- LC-MS, m/z; 3-(propan-2-yl)- 473 [M + Na]+
1H-indazol-1-yl]- 1,2,4-oxadiazol-5- yl}-1,4'- bipiperidin-1'-
yl)ethanone 414.sup.1) H H H MeO 1-(4-{3-[7- LC-MS, m/z;
methoxy-3-(propan- 467 [M + H]+ 2-yl)-1H-indazol- 1-yl]-1,2,4-
oxadiazol-5-yl}- 1,4'-bipiperidin- 1'-yl)ethanone .sup.1)Titanium
tetraisopropoxide was added to the reaction system.
[0894] The compounds in the following table (i.e. Examples 415 to
419) were prepared in the same manner as in Example 028 except that
the 3-ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and
(S)-(-)-1-tert-butoxycarbonyl-2-pyrrolidinecarbaldehyde were
replaced with the corresponding starting compound and
1-acetylpiperidin-4-one, respectively.
##STR00443##
Wherein (B-2) means each cyclic amino structure shown in the
following table, and the N-acetylpiperidine is attached to the
nitrogen atom in the cyclic amine of (B-2).
TABLE-US-00067 TABLE 67 Ex. (B-2) Compound Name .sup.1H-NMR/LC-MS,
m/z 415.sup.1) ##STR00444## 1-[4-(3-{3-[7- fluoro-3-(propan-
2-yl)-1H-indazol- 1-yl]-1,2,4- oxadiazol-5- yl}pyrrolidin-1-
yl)piperidin-1- yl]ethanone LC-MS, m/z; 441 [M + H]+ 416
##STR00445## 1-{4-[3-([{3-[7- fluoro-3-(propan- 2-yl)-1H-indazol-
1-yl]-1,2,4- oxadiazol-5- yl}methyl)azetidin- 1-yl]piperidin-1-
yl}ethanone .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15-1.33 (2H, m),
1.50 (6H, d, J = 7.0 Hz), 1.57-1.73 (2H, m), 2.07 (3H, s),
2.20-2.31 (1H, m), 2.92-3.17 (5H, m), 3.27 (2H, d, J = 6.6 Hz),
3.42-3.53 (3H, m), 3.62- 3.74 (1H, m), 4.08-4.19 (1H, m), 7.18-7.29
(2H, m), 7.56-7.62 (1H, m). LC-MS, m/z; 441[M + H]+ 417
##STR00446## 1-[4-({3-[7- fluoro-3-(propan- 2-yl)-1H-indazol-
1-yl]-1,2,4- oxadiazol-5- yl}methyl)-1,4'- bipiperidin-1'-
yl]ethanone .sup.1H-NMR (CDCl.sub.3) .delta.: 1.33-1.56 (10H, m),
1.77-2.04 (5H, m), 2.09 (3H, s), 2.15-2.30 (2H, m), 2.42-2.59 (2H,
m), 2.85-3.10 (5H, m), 3.42- 3.54 (1H, m), 3.85 (1H, d, J = 12.1
Hz), 4.66 (1H, d, J = 12.1 Hz), 7.18-7.29 (2H, m), 7.56-7.62 (1H,
m). LC-MS, m/z; 469 [M + H]+ 418.sup.1) ##STR00447##
1-(4-{3-[7-fluoro- 3-(propan-2-yl)- 1H-indazol-1-yl]-
1,2,4-oxadiazol-5- yl}-2-methyl-1,4'- bipiperidin-1'- yl}ethanone
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.09-1.15 (3H, m), 1.32-1.56 (7H,
m), 1.74-2.00 (3H, m), 2.01- 2.29 (7H, m), 2.49-2.84 (4H, m),
2.96-3.28 (2H, m), 3.31-3.55 (2H, m), 3.76- 3.99 (1H, m), 4.48-4.65
(1H, m), 7.19-7.26 (2H, m), 7.56-7.62 (1H, m). LC-MS, m/z; 469 [M +
H]+ 419.sup.1) ##STR00448## 1-{4-[3-{3-[7- fluoro-3-(propan-
2-yl)-1H-indazol- 1-yl]-1,2,4- oxadiazol-5-yl}-8- azabicyclo[3.2.1]
oct-8-yl]piperidin- 1-yl}ethanone .sup.1H-NMR (CDCl.sub.3) .delta.:
1.34-1.54 (8H, m), 1.56-1.97 (7H, m), 2.10 (3H, s), 2.27-2.45 (3H,
m), 2.57-2.66 (1H, m), 2.77-2.87 (1H, m), 3.09- 3.18 (1H, m),
3.33-3.40 (1H, m), 3.44-3.56 (3H, m), 3.77-3.86 (1H, m), 4.39- 4.48
(1H, m), 7.18-7.26 (2H, m), 7.56-7.63 (1H, m). LC-MS, m/z; 481 [M +
H]+ .sup.1)Titanium tetraisopropoxide was added to the reaction
system.
[0895] The compounds in the following table (i.e. Examples 420 to
454) were prepared in the same manner as in Example 134 except that
the
3-ethyl-6-fluoro-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and tetrahydropyrane-4-carboaldehyde were replaced
with the corresponding starting compound and aldehyde or ketone,
respectively.
##STR00449##
Wherein HX is hydrochloric acid or trifluoroacetic acid, and the
structure of R is defined in the following table. In order to
obtain each of the trifluoroacetates in the following table, the
residue was isolated/purified by reverse phase HPLC.
TABLE-US-00068 TABLE 68 .sup.1H-NMR/ LC-MS, Ex. R.sup.3 R.sup.4
R.sup.5 R.sup.6 R.sup.7 R Compound Name m/z 420 .sup.iPr H H H H
##STR00450## 1-[5-(1- cyclobutyl- piperidin-4-yl)- 1,2,4-
oxadiazol-3- yl]-3-(propan- 2-yl)-1H- indazole trifluoro- acetate
LC-MS, m/z; 366 [M + H]+ 421 .sup.iPr Cl H H H ##STR00451##
4-chloro-1-[5- (1- cyclobutyl- piperidin-4-yl)- 1,2,4- oxadiazol-3-
yl]-3-(propan- 2-yl)-1H- indazole LC-MS, m/z; 400 [M + H]+ 422
.sup.iPr Cl H H H ##STR00452## 4-chloro-3- (propan-2-yl)- 1-{5-[1-
(tetrahydro- 2H-pyran-4- yl)piperidin- 4-yl]-1,2,4- oxadiazol-3-
yl}-1H- indazole LC-MS, m/z; 430 [M + H]+ 423 .sup.iPr Me H H H
##STR00453## 1-[5-(1- cyclobutyl- piperidin-4-yl)- 1,2,4-
oxadiazol-3- yl]-4-methyl- 3-(propan-2- yl)-1H- indazole LC-MS,
m/z; 380 [M + H]+ 424 .sup.iPr Me H H H ##STR00454## 4-methyl-3-
(propan-2-yl)- 1-{5-[1- (tetrahydro- 2H-pyran-4- yl)piperidin-
4-yl]-1,2,4- oxadiazol-3- yl}-1H- indazole LC-MS, m/z; 410 [M + H]+
425 .sup.iPr H Cl H H ##STR00455## 5-chloro-1-[5- (1- cyclobutyl-
piperidin-4-yl)- 1,2,4- oxadiazol-3- yl]-3-(propan- 2-yl)-1H-
indazole LC-MS, m/z; 400 [M + H]+ 426.sup.1) .sup.iPr H Cl H H
##STR00456## 5-chloro-3- (propan-2-yl)- 1-{5-[1- (tetrahydro-
2H-pyran-4- yl)piperidin- 4-yl]-1,2,4- oxadiazol-3- yl}-1H-
indazole LC-MS, m/z; 430 [M + H]+ 427 .sup.iPr H Me H H
##STR00457## 1-[5-(1- cyclobutyl- piperidin-4-yl)- 1,2,4-
oxadiazol-3- yl]-5-methyl- 3-(propan-2- yl}-1H- indazole LC-MS,
m/z; 380 [M + H]+ 428 .sup.iPr H Me H H ##STR00458## 5-methyl-3-
(propan-2-yl)- 1-{5-[1- (tetrahydro- 2H-pyran-4- yl)piperidin-
5-yl]-1,2,4- oxadiazol-3- yl}-1H- indazole LC-MS, m/z; 410 [M + H]+
429 .sup.iPr H MeO H H ##STR00459## 1-[5-(1- cyclobutyl-
piperidin-4-yl)- 1,2,4- oxadiazol-3- yl]-5-methoxy- 3-(propan-2-
yl)-1H- indazole LC-MS, m/z; 396 [M + H]+ 430 .sup.iPr H MeO H H
##STR00460## 5-methoxy-3- (propan-2-yl)- 1-{5-[1- (tetrahydro-
2H-pyran-4- yl)piperidin- 4-yl]-1,2,4- oxadiazol-3- yl}-1H-
indazole LC-MS, m/z; 448 [M + Na]+ 431 .sup.iPr H H Cl H
##STR00461## 6-chloro-1-[5- (1- cyclobutyl- piperidin-4-yl)- 1,2,4-
oxadiazol-3- yl]-3-(propan- 2-yl)-1H- indazole LC-MS, m/z; 400 [M +
H]+ 432.sup.1) .sup.iPr H H Cl H ##STR00462## 6-chloro-3-
(propan-2-yl)- 1-{5-[1- (tetrahydro- 2H-pyran-4- yl)piperidin-
4-yl]-1,2,4- oxadiazol-3- yl}-1H- indazole LC-MS, m/z; 430 [M + H]+
433 .sup.iPr H H Me H ##STR00463## 1-[5-(1- cyclobutyl-
piperidin-4-yl)- 1,2,4- oxadiazol-3- yl]-6-methyl- 3-(propan-2-
yl)-1H- indazole LC-MS, m/z; 380 [M + H]+ 434 Et H H Me H
##STR00464## 1-[5-(1- cyclobutyl- piperidin-4-yl)- 1,2,4-
oxadiazol-3- yl]-3-ethyl-6- methyl-1H- indazole trifluoro- acetate
LC-MS, m/z; 366 [M + H]+ 435 Et H H Me H ##STR00465## 3-ethyl-6-
methyl-1-{5- [1- (tetrahydro- 2H-pyran-4- ylmethyl)piper-
idin-4-yl]- 1,2,4- oxadiazol-3- yl}-1H- indazole trifluoro- acetate
LC-MS, m/z; 432 [M + Na]+ 436 .sup.iPr H H Me H ##STR00466##
6-methyl-3- (propan-2-yl)- 1-{5-[1- (tetrahydro- 2H-pyran-4-
ylmethyl)piper- idin-4-yl]- 1,2,4- oxadiazol-3- yl}-1H- indazole
trifluoro- acetate LC-MS, m/z; 446 [M + Na]+ 437 Et H H Me H
##STR00467## 3-ethyl-6- methyl-1-{5- [1- (tetrahydro- 2H-pyran-4-
yl)piperidin- 4-yl)-1,2,4- oxadiazol-3- yl}-1H- indazole trifluoro-
acetate LC-MS, m/z; 396 [M + H]+ 438 .sup.iPr H H H Me ##STR00468##
1-[5-(1- cyclobutyl- piperidin-4-yl)- 1,2,4- oxadiazol-3-
yl]-7-methyl- 3-(propan-2- yl)-1H- indazole LC-MS, m/z; 380 [M +
H]+ 439 .sup.iPr H H H Me ##STR00469## 7-methyl-3- (propan-2-yl)-
1-{5-[1- (tetrahydro- 2H-pyran-4- yl)piperidin- 4-yl]-1,2,4-
oxadiazol-3- yl}-1H- indazole LC-MS, m/z; 432 [M + Na]+ 440
.sup.iPr H H H MeO ##STR00470## 1-[5-(1- cyclobutyl-
piperidin-4-yl)- 1,2,4- oxadiazol-3- yl]-7-methoxy- 3-(propan-2-
yl)-1H- indazole LC-MS, m/z; 396 [M + H]+ 441.sup.1) .sup.iPr H H H
MeO ##STR00471## 7-methoxy-3- (propan-2-yl)- 1-{5-[1- (tetrahydro-
2H-pyran-4- yl)piperidin- 4-yl]-1,2,4- oxadiazol-3- yl}-1H-
indazole LC-MS, m/z; 426 [M + H]+ 442.sup.1) .sup.iPr H H H F
##STR00472## 1-{5-[1-(4,4- difluorocyclo- hexyl)piperidin-
4-yl]-1,2,4- oxadiazol-3- yl}-7-fluoro- 3-(propan-2- yl)-1H-
indazole LC-MS, m/z; 448 [M + H]+ 443.sup.1) .sup.iPr H H H F
##STR00473## 7-fluoro-1-{5- [1-(1- oxidotetra- hydro-2H-
thiopyran-4- yl)piperidin- 4-yl]-1,2,4- oxadiazol-3- yl}-3-(propan-
2-yl)-1H- indazole LC-MS, m/z; 446 [M + H]+ 444.sup.1) .sup.iPr H H
H F ##STR00474## 1-{5-[1-(1,1- dioxidotetra- hydro-2H- thiopyran-4-
yl)piperidin- 4-yl]-1,2,4- oxadiazol-3- yl}-7-fluoro- 3-(propan-2-
yl)-1H- indazole LC-MS, m/z; 462 [M + H]+ 445 Et H H F F .sup.iPr
3-ethyl-6,7- difluoro-1-{5- [1-(propan-2- yl)piperidin-
4-yl]-1,2,4- oxadiazol-3- yl}-1H- indazole trifluoro- acetate
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.30- 1.50 (9H, m), 2.34- 2.47
(1H, m), 2.48- 2.60 (1H, m), 2.61- 2.79 (1H, m), 2.95- 3.12 (2H,
m), 3.12- 3.34 (2H, m), 3.42- 3.80 (5H, m), 7.12- 7.30 (1H, m),
7.40- 7.57 (1H, m). LC-MS, m/z; 376 [M + H]+ 446 Et H H F F
##STR00475## 1-[5-(1- cyclobutyl- piperidin-4-yl)- 1,.2,4-
oxadiazol-3- yl]-3-ethyl- 6,7-difluoro- 1H-indazole- trifluoro-
acetate .sup.1H-NMR (CDCl.sub.3) .delta.: 1.43 (3H, t, J = 7.6 Hz),
1.65-1.93 (2H, m), 2.07-2.70 (10H, m), 2.92-3.12 (5H, m), 3.20-3.38
(1H, m), 7.12-7.24 (1H, m), 7.40-7.52 (1H, m). LC-MS, m/z; 388 [M +
H]+ 447 Et H H F F ##STR00476## 1-[5-(1- cyclopentyl-
piperidin-4-yl)- 1,2,4- oxadiazol-3- yl]-3-ethyl- 6,7-difluoro-
1H-indazole- trifluoro- acetate .sup.1H-NMR (CDCl.sub.3) .delta.:
1.15- 2.44 (17H, m), 2.50-2.70 (1H, m), 2.90-3.28 (5H, m),
7.07-7.23 (1H, m), 7.36-7.53 (1H, m). LC-MS, m/z; 402 [M + H]+ 448
Et H H F F ##STR00477## 3-ethyl-6,7- difluoro-1-{5- [1-
(tetrahydro- 2H-pyran-4- yl)piperidin- 4-yl]-1,2,4- oxadiazol-3-
yl}-1H- indazole trifluoro- acetate .sup.1H-NMR (CDCl.sub.3)
.delta.: 1.44 (3H, t, J = 7.5 Hz), 1.80-2.08 (4H, m), 2.31-2.98
(5H, m), 3.05 (2H, q, J = 7.5 Hz), 3.12-3.83 (7H, m), 4.04-4.20
(2H, m), 7.12-7.30 (1H, m), 7.40-7.55 (1H, m). LC-MS, m/z; 418 [M +
H]+ 449 Et H H F F ##STR00478## 3-ethyl-6,7- difluoro-1-{5- [1-
(tetrahydro- 2H-pyran-4- ylmethyl)piper- idin-4-yl]- 1,2,4-
oxadiazol-3- yl}-1H- indazole trifluoro- acetate .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.30 1.54 (5H, m), 1.69- 1.85 (2H, m), 2.07-
2.23 (1H, m), 2.30- 2.78 (4H, m), 2.78- 3.11 (5H, m), 3.11- 3.49
(4H, m), 3.59- 3.79 (2H, m), 3.88- 4.10 (2H, m), 7.12- 7.30 (1H,
m), 7.40- 7.56 (1H, m). LC-MS, m/z; 432 [M + H]+ 450 .sup.iPr H H F
F .sup.iPr 6,7-difluoro- 3-(propan-2- yl)-1-{5-[1- (propan-2-
yl)piperidin- 4-yl]-1,2,4- oxadiazol-3- yl}-1H- indazole trifluoro-
acetate .sup.1H-NMR (CDCl.sub.3) .delta.: 1.38- 1.51 (12H, m),
1.38-2.52 (2H, m), 2.52-2.70 (2H, m), 2.92-3.80 (7H, m), 7.12-7.25
(1H, m), 7.45-7.60 (1H, m). LC-MS, m/z; 390 [M + H]+ 451 .sup.iPr H
H F F ##STR00479## 1-[5-(1- cyclobutyl- piperidin-4-yl)- 1,2,4-
oxadiazol-3- yl]-6,7- difluoro-3- (propan-2-yl)- 1H-indazole-
trifluoro- acetate .sup.1H-NMR (CDCl.sub.3) .delta.: 1.35- 1.52
(6H, m), 1.72- 2.05 (2H, m), 2.24- 2.63 (8H, m), 2.76- 3.15 (2H,
m), 3.30- 3.75 (5H, m), 7.09- 7.25 (1H, m), 7.43- 7.59 (1H, m).
LC-MS, m/z; 402 [M + H]+ 452 .sup.iPr H H F F ##STR00480## 1-[5-(1-
cyclopentyl- piperidin-4-yl)- 1,2,4- oxadiazol-3- yl]-6,7-
difluoro-3- (propan-2-yl)- 1H-indazole trifluoro- acetate
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.45 (6H, d, J = 6.8 Hz),
1.49-1.65 (2H, m), 1.65-1.85 (4H, m), 1.85-2.02 (2H, m), 2.18-2.30
(2H, m), 2.40-2.95 (5H, m), 3.10-3.32 (3H, m), 3.42 (1H, m, J = 6.8
Hz), 7.10-7.20 (1H, m), 7.45-7.55 (1H, m). LC-MS, m/z; 416 [M + H]+
453 .sup.iPr H H F F ##STR00481## 6,7-difluoro- 3-(propan-2-
yl)-1-{5-[1- (tetrahydro- 2H-pyran-4- ylmethyl)piper- idin-4-yl]-
1,2,4- oxadiazol-3- yl}-1H- indazole trifluoro- acetate LC-MS, m/z;
446 [M + H]+ 454 .sup.iPr H H F F ##STR00482## 6,7-difluoro-
3-(propan-2- yl)-1-{5-[1- (tetrahydro- 2H-pyran-4- yl)piperidin-
4-yl]-1,2,4- oxadiazol-3- yl}-1H- indazole trifluoro- acetate
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.47 (6H, d, J = 6.8 Hz),
1.65-1.80 (2H, m), 1.86-1.98 (2H, m), 2.12-2.28 (2H, m), 2.37-2.53
(2H, m), 2.63-2.91 (3H, m), 3.09-3.30 (3H, m), 3.34-3.50 (3H, m),
4.00-4.10 (2H, m), 7.09-7.20 (1H, m), 7.45-7.55 (1H, m). LC-MS,
m/z; 432 [M + H]+ .sup.1)Titanium tetraisopropoxide was added to
the reaction system.
[0896] The compounds in the following table (i.e. Examples 455 to
456) were prepared in the same manner as in Example 134 except that
the
3-ethyl-6-fluoro-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and tetrahydropyrane-4-carboaldehyde were replaced
with
7-fluoro-3-(propan-2-yl)-1-[5-(pyrrolidin-3-yl)-1,2,4-oxadiazol-3-yl]-1H--
indazole hydrochloride and aldehyde or ketone, respectively.
##STR00483##
Wherein the structure of R is defined in the following table.
TABLE-US-00069 TABLE 69 .sup.1H-NMR/ Ex. R Compound Name LC-MS, m/z
455 ##STR00484## 1-[5-(1-cyclobutyl- pyrrolidin-3-yl)-
1,2,4-oxadiazol-3-yl]- 7-fluoro-3-(propan-2- yl)-1H-indazole LC-MS,
m/z; 370 [M + H]+ 456 ##STR00485## 7-fluoro-3-(propan-2-
yl)-1-{5-[1-(tetrahydro- 2H-pyran-4-yl)pyrrolidin-
3-yl]-1,2,4-oxadiazol- 3-yl}-1H-indazole LC-MS, m/z; 400 [M +
H]+
Example 457
Preparation of
1-(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}--
4-hydroxy-1,4'-bipiperidin-1'-yl)ethanone
##STR00486##
[0898] The title compound was prepared in the same manner as in
Example 168 except that the
3-ethyl-1-(5-{1-[2-(piperidin-4-yl)ethyl]piperidin-4-yl}-1,2,4-oxadiazol--
3-yl)-1H-indazole bis(trifluoroacetate) and methyl chloroformate
were replaced with
4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-1,4-
'-bipiperidin-4-ol dihydrochloride and acetyl chloride,
respectively.
[0899] LC-MS, m/z; 471 [M+H]+
Preparations of Examples 458 to 466
[0900] The compounds in the following table (i.e. Examples 458 to
466) were prepared in the same manner as in Example 168 except that
the
3-ethyl-1-(5-{1-[2-(piperidin-4-yl)ethyl]piperidin-4-yl}-1,2,4-oxadiazol--
3-yl)-1H-indazole bis(trifluoroacetate) and methyl chloroformate
were replaced with the corresponding starting compound and acid
chloride (defined as R--Cl) or acetic anhydride, respectively.
##STR00487##
Wherein HX is hydrochloric acid or trifluoroacetic acid, and the
structure of R is defined in the following table. Each free form of
the compounds in the following table was obtained by omitting the
conversion step into hydrochloride in Example 168. In order to
obtain each of the trifluoroacetates, the residue was
isolated/purified by reverse phase HPLC.
TABLE-US-00070 TABLE 70 Ex. R.sup.3 R.sup.6 R.sup.7 R Compound Name
.sup.1H-NMR/LC-MS, m/z 458 .sup.iPr H H --Ac 1-(4-{3-[3- LC-MS,
m/z; (propan-2- 437 [M + H]+ yl)-1H- indazol-1- yl]-1,2,4-
oxadiazol-5- yl}-1,4'- bipiperidin- 1'- yl)ethanone trifluoro-
acetate 459 Et F F --CO.sub.2Me methyl 4-[3- .sup.1H-NMR
(CDCl.sub.3) .delta.: (3-ethyl-6,7- 1.45 (3H, t, J = 7.4
difluoro-1H- Hz), 1.62-1.80 (2H, indazol-1- m), 2.03-2.19 (2H,
yl)-1,2,4- m), 2.32-3.00 (7H, oxadiazol-5- m), 3.00-3.11 (2H,
yl]-1,4'- m), 3.11-3.60 (4H, bipiperidine- m), 3.63-3.81 (4H, 1'-
m), 4.18-4.53 (2H, carboxylate m), 7.13-7.31 (1H, trifluoro- m),
7.40-7.59 (1H, acetate m). LC-MS, m/z; 475 [M + H]+ 460 Et F F --Ac
1-{4-[3-(3- .sup.1H-NMR (CDCl.sub.3) .delta.: ethyl-6,7- 1.44 (3H,
t, J = 7.4 difluoro-1H- Hz), 1.52-1.88 (2H, indazol-1- m), 2.14
(3H, s), yl)-1,2,4- 2.20-2.76 (7H, m), oxadiazol-5- 2.85-3.90 (9H,
m), yl]-1,4'- 3.90-4.10 (1H, m), bipiperidin- 4.75-4.96 (1H, m),
1'- 7.10-7.30 (1H, m), yl}ethanone 7.40-7.60 (1H, m), trifluoro-
LC-MS, m/z; 481 acetate [M + Na]+ 461 Et F F ##STR00488##
1-{4-[3-(3- ethyl-6,7- difluoro-1H- indazol-1- yl)-1,2,4-
oxadiazol-5- yl]-1,4'- bipiperidin- 1'-yl}-2- methoxy- ethanone
trifluoro- acetate .sup.1H-NMR (CDCl.sub.3) .delta.: 1.46 (3H, t, J
= 7.6 Hz), 1.60-1.83 (2H, m), 2.09-2.30 (2H, m), 2.35-2.80 (5H, m),
3.00-3.15 (3H, m), 3.20-3.82 (9H, m), 4.00-4.23 (3H, m), 4.73-4.92
(1H, m), 7.15-7.33 (1H, m), 7.42-7.58 (1H, m). LC-MS, m/z; 489 [M +
H]+ 462 .sup.iPr Me H --Ac 1-(4-{3-[6- LC-MS, m/z; methyl-3- 451 [M
+ H]+ (propan-2- yl)-1H- indazol-1- yl]-1,2,4- oxadiazol-5-
yl}-1,4'- bipiperidin- 1'- yl}ethanone trifluoro- acetate 463
.sup.iPr F F --CO.sub.2Me methyl 4-{3- LC-MS, m/z; [6,7- 489 [M +
H]+ difluoro-3- (propan-2- yl)-1H- indazol-1- yl]-1,2,4-
oxadiazol-5- yl}-1,4'- bipiperidine 1'- carboxylate trifluoro-
acetate 464 .sup.iPr F F --Ac 1-(4-{3-[6, .sup.1H-NMR (CD.sub.3OD)
.delta.: 7-difluoro-3- 1.48 (6H, d, J = (propan-2- 7.2 Hz),
1.60-1.89 yl)-1H- (2H, m), 2.10-2.35 indazol-1- (7H, m), 2.35-2.78
yl]-1,2,4- (3H, m), 3.12-3.30 oxadiazol-5- (2H, m), 3.40-3.69
yl}-1,4'- (4H, m), 3.69-3.85 bipiperidin- (2H, m), 4.04-4.20 1'-
(1H, m), 4.65-4.80 yl}ethanone (1H, m), 7.25-7.40 trifluoro- (1H,
m), 7.69-7.80 acetate (1H, m). 465 .sup.iPr F F ##STR00489##
1-(4-{3-[6, 7-difluoro-3- (propan-2- yl)-1H- indazol-1- yl]-1,2,4-
oxadiazol-5- yl}-1,4'- bipiperidin- 1'-yl)-2- methoxy- ethanone
trifluoro- acetate .sup.1H-NMR (CDCl.sub.3) .delta.: 1.48 (6H, t, J
= 7.2 Hz), 1.54-1.82 (2H, m), 2.04-2.27 (2H, m), 2.27-2.79 (5H, m),
2.98-3.15 (1H, m), 3.15-3.80 (10H, m), 3.98-4.20 (3H, m), 4.70-4.88
(1H, m), 7.10-7.25 (1H, m), 7.47-7.60 (1H, m). LC-MS, m/z; 525 [M +
Na]+ 466 .sup.iPr F F -Ms 4-{3-[7- .sup.1H-NMR (CDCl.sub.3)
.delta.: fluoro-3- 1.50 (6H, d, J = 7.0 (propan-2- Hz), 1.63-1.77
(2H, yl)-1H- m), 1.84-1.96 (2H, indazol-1- m), 1.99-2.11 (2H,
yl]-1,2,4- m), 2.15-2.25 (2H, oxadiazol-5- m), 2.33-2.51 (3H,
yl}-1'- m), 2.66-2.77 (2H, (methyl- m), 2.79 (3H, s),
sulfonyl)-1,4'- 2.93-3.12 (3H, m), bipiperidine 3.43-3.53 (1H, m),
trifluoro- 3.85 (2H, d, J = 12.3 acetate Hz), 7.18-7.29 (2H, m),
7.56-7.63 (1H, m). LC-MS, m/z; 491 [M + H]+
Preparations of Examples 467 to 494
[0901] The compounds in the following table (i.e. Examples 467 to
494) were prepared in the same manner as in Example 168 except that
the
3-ethyl-1-(5-{1-[2-(piperidin-4-yl)ethyl]piperidin-4-yl}-1,2,4-oxadiazol--
3-yl)-1H-indazole bis(trifluoroacetate) and methyl chloroformate
were replaced with the corresponding starting compound and acid
chloride (defined as R--Cl) or acetic anhydride, respectively.
##STR00490##
Wherein HX is hydrochloric acid or trifluoroacetic acid,
(R.sup.12-1) means each cyclic amino structure shown in the
following table, and the structure of R is defined in the following
table. R is attached to the nitrogen atom in the cyclic amine of
(R.sup.12-1). Each free form of the compounds in the following
table was obtained by omitting the conversion step into
hydrochloride in Example 168. In order to obtain each of the
trifluoroacetates, the residue was isolated/purified by reverse
phase HPLC.
TABLE-US-00071 TABLE 71 Compound .sup.1H-NMR/ Ex. R.sup.3 R.sup.6
R.sup.7 (R.sup.12-1) R Name LC-MS, m/z 467 .sup.iPr H H
##STR00491## --Ac 1-{3-[(4- {3-[3- (propan-2- yl)-1H- indazol-1-
yl]-1,2,4- oxadiazol- 5- yl}piper- idin-1- yl)methyl] azetidin-1-
yl}ethanone trifluoro- acetate LC-MS, m/z; 445 [M + Na]+ 468 469 Et
Et F F F F ##STR00492## --Ac ##STR00493## 1-[3-({4- [3-(3-
ethyl-6,7- difluoro- 1H-indazol- 1-yl)- 1,2,4- oxadiazol- 5-
yl]piper- idin-1- yl}methyl) azetidin-1- yl]ethanone trifluoro-
acetate 1-[3-({4- [3-(3- ethyl-6,7- difluoro- 1H-indazol- 1-yl)-
1,2,4- oxadiazol- 5- yl]piper- idin-1- yl}methyl) azetidin-1-
yl]-2- methoxy- ethanone trifluoro- acetate .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.43 (3H, t, J = 7.6 Hz), 1.86 (3H, s),
2.30-2.68 (4H, m), 3.04 (2H, q, J = 7.6 Hz), 3.10- 3.90 (9H, m),
3.93- 4.03 (1H, m), 4.18- 4.30 (1H, m), 4.30- 4.43 (1H, m), 7.12-
7.26 (1H, m), 7.40- 7.55 (1H, m). LC-MS, m/z; 445 [M + H]+ LC-MS,
m/z; 475 [M + H]+ 470 471 472 Et .sup.iPr .sup.iPr F Me F F H F
##STR00494## --CO.sub.2Me --Ac --Ac methyl 3- ({4-[3-(3- ethyl-6,7-
difluoro- 1H-indazol- 1-yl)- 1,2,4- oxadiazol- 5- yl]piper- idin-1-
yl}methyl) azetidine-1- carboxylate trifluoro- acetate 1-{3-[(4-
{3-[6- methyl-3- (propan-2- yl)-1H- indazol-1- yl]-1,2,4-
oxadiazol- 5- yl}piper- idin-1- yl)methyl] azetidin-1- yl}ethanone
trifluoro- acetate 1-{3-[(4- {3-[6,7- difluoro-3- (propan-2-
yl)-1H- indazol-1- yl]-1,2,4- oxadiazol- 5- yl}piper- idin-1-
yl)methyl] azetidin-1- yl}ethanone trifluoro- acetate LC-MS, m/z;
461 [M + H]+ LC-MS, m/z; 437 [M + H]+ .sup.1H-NMR (CD.sub.3OD)
.delta.: 1.46 (6H, d, J = 7.2 Hz), 1.87 (3H, s), 2.18-2.59 (4H, m),
3.15-3.37 (3H, m), 3.41-3.84 (7H, m), 4.02-4.1 (1H, m), , 4.16-4.28
(1H, m), 4.40-4.45 (1H, m), 7.25-7.40 (1H, m), 7.69-7.80 (1H, m).
473 474 .sup.iPr .sup.iPr F F F F ##STR00495## ##STR00496##
--CO.sub.2Me 1-{3-[(4- {3-[6,7- difluoro-3- (propan-2- yl)-1H-
indazol-1- yl]-1,2,4- oxadiazol- 5- yl}piper- idin-1- yl)methyl]
azetidin-1- yl}-2- methoxy- ethanone trifluoro- acetate methyl 3-
[(4-{3-[6, 7-difluoro- 3-(propan- 2-yl)-1H- indazol-1- yl]-1,2,4-
oxadiazol- 5- yl}piper- idin-1- yl)methyl] azetidine-1- carboxylate
trifluoro- acetate .sup.1H-NMR (CD.sub.3OD) .delta.: 1.46 (6H, d, J
= 7.2 Hz), 2.18- 2.59 (4H, m), 3.19- 3.37 (3H, m), 3.38 (3H, s),
3.41-3.84 (7H, m), 4.02-4.1 (1H, m), , 4.16-4.28 (1H, m), 4.40-4.5
(1H, m), 7.25-7.40 (1H, m), 7.69-7.80 (1H, m). .sup.1H-NMR
(CD.sub.3OD) .delta.: 1.46 (6H, d, J = 7.2 Hz), 2.18- 2.59 (4H, m),
3.15- 3.37 (3H, m), 3.4- 3.6 (4H, m), 3.61- 3.9 (7H, m), 4.15- 4.38
(2H, m), 7.25- 7.40 (1H, m), 7.69- 7.80 (1H, m). 475 .sup.iPr H H
##STR00497## --Ac 1-{4-[(4- {3-[3- (propan-2- yl)-1H- indazol-1-
yl]-1,2,4- oxadiazol 5- yl}piper- idin-1- yl)methyl] piperidin-1-
yl}ethanone trifluoro- acetate LC-MS, m/z; 451 [M + H]+ 476 477 Et
Et F F F F ##STR00498## --CO.sub.2Me ##STR00499## methyl 4-
({4-[3-(3- ethyl-6,7- difluoro- 1H-indazol- 1-yl)- 1,2,4-
oxadiazol- 5- yl]piper- idin-1- yl}methyl) piperidin- 1-
carboxylate trifluoro- acetate 1-[4-({4- [3-(3- ethyl-6,7-
difluoro- 1H-indazol- 1-yl)- 1,2,4- oxadiazol- 5- yl]piper- idin-1-
yl}methyl) piperidin-1- yl]-2- methoxy- ethanone trifluoro- acetate
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.00-1.18 (2H, m), 1.42 (3H, t, J
= 7.6 Hz), 1.55- 1.85 (4H, m), 1.94- 2.30 (8H, m), 2.68- 2.81 (2H,
m), 2.82- 3.00 (2H, m), 3.04 (2H, q, J = 7.6 Hz), 3.68 (3H, s),
3.95- 4.30 (2H, br), 7.10- 7.21 (1H, m), 7.40- 7.50 (1H, m). LC-MS,
m/z; 489 [M + H]+ .sup.1H-NMR (CDCl.sub.3) .delta.: 1.17-1.38 (2H,
m), 1.43 (3H, t, J = 7.6 Hz), 1.76- 2.25 (3H, m), 2.30- 2.80 (5H,
m), 2.80- 3.38 (7H, m), 3.40 (3H, s), 3.50-3.92 (4H, m), 4.00-4.17
(2H, m), 4.50-4.69 (1H, m), 7.10-7.25 (1H, m), 7.40-7.56 (1H, m).
LC-MS, m/z; 503 [M + H]+ 478 Et F F ##STR00500## --Ac 1-[4-({4-
[3-(3- ethyl-6,7- difluoro- 1H-indazol- 1-yl)- 1,2,4- oxadiazol- 5-
yl]piper- idin-1- yl}methyl) piperidin-1- yl]ethanone trifluoro-
acetate LC-MS, m/z; 473 [M + H]+ 479 480 .sup.iPr .sup.iPr Me F H F
##STR00501## --Ac --Ac 1-{4-[(4- {3-[6- methyl-3- (propan-2-
yl)-1H- indazol-1- yl]-1,2,4- oxadiazol- 5- yl}piper- idin-1-
yl)methyl] piperidin-1- yl}ethanone trifluoro- acetate 1-{4-[(4-
{3-[6,7- difluoro-3- (propan-2- yl)-1H- indazol-1- yl]-1,2,4-
oxadiazol- 5- yl}piper- idin-1- yl)methyl] piperidin-1- yl}ethanone
trifluoro- acetate LC-MS, m/z; 487 [M + Na]+ LC-MS, m/z; 487 [M +
H]+ 481 .sup.iPr F F ##STR00502## ##STR00503## 1-{4-[(4- {3-[6,7-
difluoro-3- (propan-2- yl)-1H- indazol-1- yl]-1,2,4- oxadiazol- 5-
yl}piper- idin-1- yl)methyl] piperidin-1- yl}-2- methoxy- ethanone
trifluoro- acetate .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12-1.35 (2H,
m), 1.35-1.54 (6H, m), 1.77-2.03 (2H, m), 2.07-2.25 (1H, m),
2.31-2.71 (5H, m), 2.90-3.14 (4H, m), 3.17-3.50 (2H, m), 3.38 (3H,
s), 3.60- 3.90 (4H, m), 4.00- 4.20 (2H, m), 4.45- 4.64 (1H, m),
7.09- 7.21 (1H, m), 7.41- 7.58 (1H, m). LC-MS, m/z; 539 [M + Na]+
482 .sup.iPr F F ##STR00504## --CO.sub.2Me methyl 4- [(4-{3- [6,7-
difluoro-3- (propan-2- yl)-1H- indazol-1- yl]-1,2,4- oxadiazol- 5-
yl}piper- idin-1- yl)methyl] piperidine- 1- carboxylate trifluoro-
acetate LC-MS, m/z; 525 [M + Na]+ 483 484 .sup.iPr .sup.iPr H H F F
##STR00505## --Ac --CO.sub.2Me 1-{2-[(4- {3-[7- fluoro-3-
(propan-2- yl)-1H- indazol-1- yl]-1,2,4- oxadiazol- 5- yl}piper-
idin-1- yl)methyl] morpholin-4- yl}ethanone methyl 2- [(4-{3-[7-
fluoro-3- (propan-2- yl)-1H- indazol-1- yl]-1,2,4- oxadiazol- 5-
yl}piper- idin-1- yl)methyl] morpholine- 4- carboxylate LC-MS, m/z;
471 [M + H]+ LC-MS, m/z; 487 [M + H]+ 485 486 .sup.iPr .sup.iPr H H
F F ##STR00506## ##STR00507## -Ms 2-[(4-{3- [7-fluoro- 3-(propan-
2-yl)-1H- indazol-1- yl]-1,2,4- oxadiazol- 5- yl}piper- idin-1-
yl)methyl]- N,N- dimethyl- morpholine-4- carboxamide 7-fluoro-1-
[5-(1-{[4- (methyl- sulfonyl)mor- pholin-2- yl]methyl} piperidin-4-
yl)-1,2,4- oxadiazol- 3-yl]-3- (propan-2- yl)-1H- indazole LC-MS,
m/z; 500 [M + H]+ LC-MS, m/z; 507 [M + H]+ 487 .sup.iPr H F
##STR00508## --Ac 1-(4-{3-[7- fluoro-3- (propan-2- yl)-1H-
indazol-1- yl]-1,2,4- oxadiazol- 5-yl}-4'- methyl- 1,4'- bipiper-
idin-1'- yl)ethanone .sup.1H-NMR (CDCl.sub.3) .delta.: 0.95 (3H,
s), 1.24- 1.47 (2H, m), 1.50 (6H, dd, J = 7.0, 0.6 Hz), 1.82- 2.38
(11H, m), 2.92- 3.11 (3H, m), 3.19- 3.59 (4H, m), 3.86- 3.99 (1H,
m), 7.16- 7.29 (2H, m), 7.55- 7.63 (1H, m). LC-MS, m/z; 469 [M +
H]+ 488 .sup.iPr H F ##STR00509## -Ms 4-{3-[7- fluoro-3- (propan-2-
yl)-1H- indazol-1- yl]-1,2,4- oxadiazol- 5-yl}-4'- methyl-1'-
(methyl- sulfonyl)- 1,4'- bipiperidine .sup.1H-NMR (CDCl.sub.3)
.delta.: 0.96 (3H, s), 1.47- 1.61 (8H, m), 1.90- 2.08 (4H, m),
2.15- 2.35 (4H, m), 2.80 (3H, s), 2.94-3.16 (5H, m), 3.36-3.55 (3H,
m), 7.18-7.29 (2H, m), 7.56-7.62 (1H, m). LC-MS, m/z; 505 [M + H]+
489 .sup.iPr H F ##STR00510## ##STR00511## 4-{3-[7- fluoro-3-
(propan-2- yl)-1H- indazol-1- yl]-1,2,4- oxadiazol- 5-yl}- N,N,4'-
trimethyl- 1,4'- bipiper- idine-1'- carboxamide .sup.1H-NMR
(CDCl.sub.3) .delta.: 0.94 (3H, s), 1.39- 1.57 (8H, m), 1.77- 1.87
(2H, m), 1.92- 2.08 (2H, m), 2.11- 2.35 (4H, m), 2.81 (6H, s),
2.97-3.10 (3H, m), 3.15-3.37 (4H, m), 3.44-3.53 (1H, m), 7.17-7.29
(2H, m), 7.55-7.63 (1H, m). LC-MS, m/z; 498 [M + H]+ 490 .sup.iPr H
F ##STR00512## ##STR00513## 1-(4-{3-[7- fluoro-3- (propan-2-
yl)-1H- indazol-1- yl]-1,2,4- oxadiazol- 5-yl}-4'- methyl- 1,4'-
bipiper- idin-1'-yl)-2- methoxy- ethanone .sup.1H-NMR (CDCl.sub.3)
.delta.: 0.93 (3H, s), 1.28- 1.43 (2H, m), 1.47 (6H, d, J = 7.0
Hz), 1.83-2.07 (4H, m), 2.10-2.36 (4H, m), 2.90-3.09 (3H, m),
3.17-3.32 (1H, m), 3.36-3.53 (6H, m), 3.88-3.99 (1H, m), 4.08 (2H,
dd, J = 17.5, 13.3 Hz), 7.15- 7.25 (2H, m), 7.53- 7.60 (1H, m).
LC-MS, m/z; 499 [M + H]+ 491 Et H F ##STR00514## --Ac 1-{4-[3-(3-
ethyl-7- fluoro-1H- indazol-1- yl)-1,2,4- oxadiazol- 5-yl]-4'-
methyl- 1,4'- bipiper- idin-1'- yl}ethanone .sup.1H-NMR
(CDCl.sub.3) .delta.: 0.93 (3H, s), 1.25- 1.46 (5H, m), 1.81- 2.08
(7H, m), 2.11- 2.34 (4H, m), 2.91- 3.10 (5H, m), 3.14- 3.55 (3H,
m), 3.84- 3.99 (1H, m), 7.17- 7.27 (2H, m), 7.48- 7.53 (1H, m).
LC-MS, m/z; 455 [M + H]+ 492 493 Et Et H H F F ##STR00515## -Ms
##STR00516## 4-[3-(3- ethyl-7- fluoro-1H- indazol-1- yl)-1,2,4-
oxadiazol- 5-yl]-4'- methyl-1'- (methyl- sulfonyl)-1,4'-
bipiperidine 4-[3-(3- ethyl-7- fluoro-1H- indazol-1- yl)-1,2,4-
oxadiazol- 5-yl]- N,N,4'- trimethyl- 1,4'- bipiper- idine-1'-
carboxamide .sup.1H-NMR (CDCl.sub.3) .delta.: 0.93 (3H, s), 1.38-
1.53 (5H, m), 1.89- 2.05 (4H, m), 2.13- 2.31 (4H, m), 2.78 (3H, s),
2.89-3.13 (7H, m), 3.33-3.45 (2H, m), 7.18-7.29 (2H, m), 7.49-7.54
(1H, m). LC-MS, m/z; 491 [M + H]+ .sup.1H-NMR (CDCl.sub.3) .delta.:
0.91 (3H, s), 1.31- 1.51 (5H, m), 1.73- 1.85 (2H, m), 1.89- 2.05
(2H, m), 2.08- 2.32 (4H, m), 2.79 (6H, s), 2.92-3.10 (5H, m),
3.12-3.34 (4H, m), 7.18-7.26 (2H, m), 7.48-7.53 (1H, m). LC-MS,
m/z; 483 [M + H]+ 494 Et H F ##STR00517## ##STR00518## 1-{4-[3-(3-
ethyl-7- fluoro-1H- indazol-1- yl)-1,2,4- oxadiazol- 5-yl]-4'-
methyl- 1,4'- bipiper- idin-1'-yl}-2- methoxy- ethanone .sup.1H-NMR
(CDCl.sub.3) .delta.: 0.93 (3H, s), 1.28- 1.47 (5H, m), 1.81- 2.07
(4H, m), 2.12- 2.35 (4H, m), 2.91- 3.11 (5H, m), 3.17- 3.31 (1H,
m), 3.34- 3.52 (5H, m), 3.88- 4.00 (1H, m), 4.00- 4.17 (2H, m),
7.16- 7.27 (2H, m), 7.48- 7.54 (1H, m). LC-MS, m/z; 485 [M +
H]+
Preparations of Examples 495 to 506
[0902] The compounds in the following table (i.e. Examples 495 to
506) were prepared in the same manner as in Example 168 except that
the
3-ethyl-1-(5-{1-[2-(piperidin-4-yl)ethyl]piperidin-4-yl}-1,2,4-oxadiazol--
3-yl)-1H-indazole bis(trifluoroacetate) and methyl chloroformate
were replaced with the corresponding starting compound and acid
chloride (defined as R--Cl) or acetic anhydride, respectively.
##STR00519##
Wherein (R.sup.12-1) means each cyclic amino structure shown in the
following table, and the structure of R is defined in the following
table. R is attached to the nitrogen atom in the cyclic amine of
(R.sup.12-1). Each free form of the compounds in the following
table was obtained by omitting the conversion step into
hydrochloride in Example 168.
TABLE-US-00072 TABLE 72 Ex. (R.sup.12-1) R Compound Name
.sup.1H-NMR/LC-MS, m/z 495 ##STR00520## --Ac 1-{4-[(3R)-3-({3-
[7-fluoro-3- (propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}methyl)pyrrolidin- 1-yl]piperidin-1- yl}ethanone .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.39-1.99 (12H, m), 2.08 (3H, s), 2.12- 3.17
(10H, m), 3.41- 3.55 (1H, m), 3.78 (1H, d, J = 13.6 Hz), 4.43 (1H,
d, J = 10.5 Hz), 7.18-7.30 (2H, m), 7.56-7.63 (1H, m). LC-MS, m/z;
455 [M + H]+ 496 --Ms 7-fluoro-1-[5- ({(3R)-1-[1- (methylsulfonyl)
piperidin-4- yl]pyrrolidin-3- yl}methyl)-1,2,4- oxadiazol-3-yl]-3-
(propan-2-yl)-1H- indazole .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50
(6H, d, J = 7.0 Hz), 1.59-1.74 (3H, m), 1.87-1.99 (2H, m),
2.09-2.27 (2H, m), 2.42-2.51 (1H, m), 2.57-2.96 (9H, m), 3.08 (2H,
d, J = 6.8 Hz), 3.42-3.54 (1H, m), 3.56-3.68 (2H, m), 7.18-7.30
(2H, m), 7.56-7.63 (1H, m). LC-MS, m/z; 491 [M + H]+ 497
##STR00521## --Ac 1-[(2S)-2-{[(3R)-3- ({3-[7-fluoro-3-
(propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}methyl)pyrrolidin- 1-yl]methyl}pyrrolidin- 1-yl]ethanone
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (6H, d, J = 7.0 Hz),
1.55-1.71 (1H, m), 1.80-2.20 (8H, m), 2.32-2.88 (7H, m), 3.01-3.11
(2H, m), 3.31-3.57 (3H, m), 3.82-3.93 (0.4H, m, rotamer), 4.14-
4.27 (0.6H, m, rotamer), 7.18-7.27 (2H, m), 7.55-7.63 (1H, m).
LC-MS, m/z; 455 [M + H]+ 498 --Ms 7-fluoro-1-(5- {[(3R)-1-{[(2S)-1-
(methylsulfonyl) pyrrolidin-2- yl]methyl}pyrrolidin- 3-yl]methyl}-
1,2,4-oxadiazol-3- yl)-3-(propan-2- yl)-1H-indazole .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.50 (6H, d, J = 7.1 Hz), 1.57-1.67 (1H, m),
1.84-2.00 (4H, m), 2.06-2.17 (1H, m), 2.46-2.68 (4H, m), 2.72-2.83
(3H, m), 2.88 (3H, s), 3.02-3.08 (2H, m), 3.29-3.41 (2H, m),
3.44-3.53 (1H, m), 3.75-3.85 (1H, m), 7.19-7.27 (2H, m), 7.56-7.62
(1H, m). LC-MS, m/z; 491 [M + H]+ 499 ##STR00522## --Ac
1-[(2R)-2-{[(3R)-3- ({3-[7-fluoro-3- (propan-2-yl)-1H-
indazol-1-yl]- 1,2,4-oxadiazol-5- yl}methyl)pyrrolidin-
1-yl]methyl}pyrrolidin- 1-yl]ethanone .sup.1H-NMR (CDCl.sub.3)
.delta.: 1.50 (6H, d, J = 7.0 Hz), 1.55-1.70 (1H, m), 1.77-2.20
(8H, m), 2.32-2.89 (7H, m), 2.98-3.14 (2H, m), 3.31-3.56 (3H, m),
3.80-3.95 (0.4H, m, rotamer), 4.13- 4.26 (0.6H, m, rotamer),
7.18-7.29 (2H, m), 7.55-7.63 (1H, m). LC-MS, m/z; 455 [M + H]+ 500
##STR00523## --Ms 7-fluoro-1-(5- {[(3R)-1-{[(2R)-1-
(methylsulfonyl) pyrrolidin-2- yl]methyl}pyrrolidin- 3-yl]methyl}-
1,2,4-oxadiazol-3- yl)-3-(propan-2- yl)-1H-indazole .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.50 (6H, d, J = 7.0 Hz), 1.54-1.69 (1H, m),
1.82-2.00 (4H, m), 2.05-2.21 (1H, m), 2.43-2.86 (7H, m), 2.88 (3H,
s), 3.02-3.10 (2H, m), 3.29-3.41 (2H, m), 3.43-3.54 (1H, m),
3.75-3.87 (1H, m), 7.18-7.27 (2H, m), 7.56-7.63 (1H, m). LC-MS,
m/z; 491 [M + H]+ 501 ##STR00524## --Ac 1-(3-{[(3R)-3-({3-
[7-fluoro-3- (propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}methyl)pyrrolidin- 1-yl]methyl}azetidin- 1-yl)ethanone
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (6H, d, J = 7.2 Hz),
1.56-1.72 (1H, m), 1.83 (3H, d, J = 1.7 Hz), 2.06-2.24 (1H, m),
2.37-2.85 (8H, m), 3.06 (2H, d, J = 6.4 Hz), 3.41- 3.55 (1H, m),
3.59- 3.68 (1H, m), 3.75- 3.82 (1H, m), 4.02- 4.23 (2H, m), 7.18-
7.30 (2H, m), 7.55- 7.63 (1H, m). LC-MS, m/z; 441 [M + H]+ 502 --Ms
7-fluoro-1-(5- {[(3R)-1-{[1- (methylsulfonyl) azetidin-3-
yl]methyl}pyrrolidin- 3-yl]methyl}- 1,2,4-oxadiazol-3-
yl)-3-(propan-2- yl)-1H-indazole .sup.1H-NMR (CDCl.sub.3) .delta.:
1.50 (6H, d, J = 7.0 Hz), 1.57-1.71 (1H, m), 2.07-2.22 (1H, m),
2.36-2.82 (8H, m), 2.84 (3H, s), 3.05 (2H, d, J = 7.2 Hz),
3.41-3.54 (1H, m), 3.66 (2H, dd, J = 7.8, 5.8 Hz), 3.93- 4.03 (2H,
m), 7.19- 7.29 (2H, m), 7.56- 7.63 (1H, m). LC-MS, m/z; 477 [M +
H]+ 503 ##STR00525## --Ac 1-[(3S)-3-{[(3R)-3- ({3-[7-fluoro-3-
(propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}methyl)pyrrolidin- 1-yl]methyl}pyrrolidin- 1-yl]ethanone
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.44-1.80 (8H, m), 1.95-2.23 (5H,
m), 2.29-2.86 (8H, m), 3.02-3.21 (3H, m), 3.31-3.74 (4H, m),
7.18-7.28 (2H, m), 7.56-7.62 (1H, m). LC-MS, m/z; 455 [M + H]+ 504
##STR00526## --Ms 7-fluoro-1-(5- {[(3R)-1-{[(3S)-1-
(methylsulfonyl) pyrrolidin-3- yl]methyl}pyrrolidin- 3-yl]methyl}-
1,2,4-oxadiazol-3- yl)-3-(propan-2- yl)-1H-indazole .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.50 (6H, d, J = 7.0 Hz), 1.55-1.77 (2H, m),
1.99-2.24 (2H, m), 2.36-2.80 (8H, m), 2.82 (3H, s), 3.01-3.13 (3H,
m), 3.24-3.56 (4H, m), 7.18-7.30 (2H, m), 7.56-7.63 (1H, m). LC-MS,
m/z; 491 [M + H]+ 505 ##STR00527## --Ac 1-[(3R)-3-{[(3R)-3-
({3-(7-fluoro-3- (propan-2-yl)-1H- indazol-1-yl]-
1,2,4-oxadiazol-5- yl}methyl)pyrrolidin- 1-yl]methyl}pyrrolidin-
1-yl]ethanone .sup.1H-NMR (CDCl.sub.3) .delta.: 1.49 (6H, d, J =
7.1 Hz), 1.52-1.78 (2H, m), 1.92-2.21 (5H, m), 2.29-2.83 (8H, m),
3.01-3.19 (3H, m), 3.30-3.73 (4H, m), 7.17-7.27 (2H, m), 7.55-7.61
(1H, m). LC-MS, m/z; 455 [M + H]+ 506 --Ms 7-fluoro-1-(5-
{[(3R)-1-{[(3R)-1- (methylsulfonyl) pyrrolidin-3-
yl]methyl}pyrrolidin- 3-yl]methyl}- 1,2,4-oxadiazol-3-
yl)-3-(propan-2- yl)-1H-indazole .sup.1H-NMR (CDCl.sub.3) .delta.:
1.50 (6H, d, J = 7.1 Hz), 1.57-1.75 (3H, m), 2.03-2.20 (2H, m),
2.38-2.85 (10H, m), 3.03-3.11 (3H, m), 3.27-3.54 (4H, m), 7.19-7.29
(2H, m), 7.56-7.63 (1H, m). LC-MS, m/z; 491 [M + H]+
Preparations of Examples 507 to 518
[0903] The compounds in the following table (i.e. Examples 507 to
518) were prepared in the same manner as in Example 168 except that
the
3-ethyl-1-(5-{1-[2-(piperidin-4-yl)ethyl]piperidin-4-yl}-1,2,4-oxadiazol--
3-yl)-1H-indazole bis(trifluoroacetate) and methyl chloroformate
were replaced with the corresponding starting compound and acid
chloride (defined as R--Cl) or acetic anhydride, respectively.
##STR00528##
[0904] Wherein (R.sup.12-1) means each cyclic amino structure shown
in the following table, and the structure of R is defined in the
following table. R is attached to the nitrogen atom in the cyclic
amine of (R.sup.12-1). Each free form of the compounds in the
following table was obtained by omitting the conversion step into
hydrochloride in Example 168.
TABLE-US-00073 TABLE 73 Ex. (R.sup.12-1) R Compound Name
.sup.1H-NMR/LC-MS, m/z 507 ##STR00529## --Ac 1-{4-[(3S)-3-({3-
[7-fluoro-3- (propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}methyl)pyrrolidin- 1-yl]piperidin- 1-yl}ethanone .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.39- 1.99 (12H, m), 2.08 (3H, s), 2.12-3.17
(10H, m), 3.41-3.55 (1H, m), 3.78 (1H, d, J = 13.6 Hz), 4.43 (1H,
d, J = 10.5 Hz, 7.18- 7.30 (2H, m), 7.56-7.63 (1H, m). LC-MS, m/z;
455 [M + H]+ 508 --Ms 7-fluoro-1-[5- ({(3S)-1-[1- (methylsulfonyl)
piperidin-4- yl]pyrrolidin-3- yl}methyl)-1,2,4- oxadiazol-3-yl]-3-
(propan-2-yl)-1H- indazole .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50
(6H, d, J = 7.0 Hz), 1.59-1.74 (3H, m), 1.87-1.99 (2H, m),
2.09-2.27 (2H, m), 2.42-2.51 (1H, m), 2.57-2.96 (9H, m), 3.08 (2H,
d, J = 6.8 Hz), 3.42-3.54 (1H, m), 3.56-3.68 (2H, m), 7.18-7.30
(2H, m), 7.56-7.63 (1H, m). LC-MS, m/z; 491[M + H]+ 509
##STR00530## --Ac 1-[(2S)-2-{[(3S)- 3-({3-[7-fluoro-3-
(propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}methyl)pyrrolidin- 1-yl]methyl)pyrrolidin- 1-yl]ethanone
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (6H, d, J = 7.0 Hz),
1.55-1.70 (1H, m), 1.77-2.20 (8H, m), 2.32-2.89 (7H, m), 2.98-3.14
(2H, m), 3.31-3.56 (3H, m), 3.80-3.95 (0.4H, m, rotamer), 4.13-4.26
(0.6H, m, rotamer), 7.18-7.29 (2H, m), 7.55-7.63 (1H, m). LC-MS,
m/z; 455 [M + H]+ 510 --Ms 7-fluoro-1-(5- {[(3S)-1-{[(2S)-1-
(methylsulfonyl) pyrrolidin-2- yl]methyl}pyrrolidin- 3-yl]methyl}-
1,2,4-oxadiazol-3- yl)-3-(propan-2- yl)-1H-indazole .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.50 (6H, d, J = 7.0 Hz), 1.54-1.69 (1H, m),
1.82-2.00 (4H, m), 2.05-2.21 (1H, m), 2.43-2.86 (7H, m), 2.88 (3H,
s), 3.02-3.10 (2H, m), 3.29-3.41 (2H, m), 3.43-3.54 (1H, m),
3.75-3.87 (1H, m), 7.18-7.27 (2H, m), 7.56-7.63 (1H, m). LC-MS,
m/z; 491 [M + H]+ 511 ##STR00531## --Ac 1-[(2R)-2-{[(3S)-
3-({3-[7-fluoro-3- (propan-2-yl)-1H- indazol-1-yl]-
1,2,4-oxadiazol-5- yl}methyl)pyrrolidin- 1-yl]methyl}pyrrolidin-
1-yl]ethanone .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (6H, d, J =
7.0 Hz), 1.55-1.71 (1H, m), 1.80-2.20 (8H, m), 2.32-2.88 (7H, m),
3.01-3.11 (2H, m), 3.31-3.57 (3H, m), 3.82-3.93 (0.4H, m, rotamer),
4.14-4.27 (0.6H, m, rotamer), 7.18-7.27 (2H, m), 7.55-7.63 (1H, m).
LC-MS, m/z; 455 [M + H]+ 512 --Ms 7-fluoro-1-(5- {[(3S)-1-{[(2R)-1-
(methylsulfonyl) pyrrolidin-2- yl]methyl}pyrrolidin- 3-yl]methyl}-
1,2,4-oxadiazol-3- yl)-3-(propan-2- yl)-1H-indazole .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.50 (6H, d, J = 7.1 Hz), 1.57-1.67 (1H, m),
1.84-2.00 (4H, m), 2.06-2.17 (1H, m), 2.46-2.68 (4H, m), 2.72-2.83
(3H, m), 2.88 (3H, s), 3.02-3.08 (2H, m), 3.29-3.41 (2H, m),
3.44-3.53 (1H, m), 3.75-3.85 (1H, m), 7.19-7.27 (2H, m), 7.56-7.62
(1H, m). LC-MS, m/z; 491 [M + H]+ 513 ##STR00532## --Ac
1-(3-{[(3S)-3-({3- [7-fluoro-3- (propan-2-yl)-1H- indazol-1-yl]-
1,2,4-oxadiazol-5- yl}methyl)pyrrolidin- 1-yl]methyl}azetidin-
1-yl)ethanone .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (6H, d, J =
7.2 Hz), 1.56-1.72 (1H, m), 1.83 (3H, d, J = 1.7 Hz), 2.06-2.24
(1H, m), 2.37-2.85 (8H, m), 3.06 (2H, d, J = 6.4 Hz), 3.41-3.55
(1H, m), 3.59-3.68 (1H, m), 3.75-3.82 (1H, m), 4.02-4.23 (2H, m),
7.18-7.30 (2H, m), 7.55-7.63 (1H, m). LC-MS, m/z; 441 [M + H]+ 514
--Ms 7-fluoro-1-(5- {[(3S)-1-{[1- (methylsulfonyl) azetidin-3-
yl]methyl}pyrrolidin- 3-yl]methyl}- 1,2,4-oxadiazol-3-
yl)-3-(propan-2- yl)-1H-indazole .sup.1H-NMR (CDCl.sub.3) .delta.:
1.50 (6H, d, J = 7.0 Hz), 1.57-1.71 (1H, m), 2.07-2.22 (1H, m),
2.36-2.82 (8H, m), 2.84 (3H, s), 3.05 (2H, d, J = 7.2 Hz),
3.41-3.54 (1H, m), 3.66 (2H, dd, J = 7.8, 5.8 Hz), 3.93- 4.03 (2H,
m), 7.19-7.29 (2H, m), 7.56-7.63 (1H, m). LC-MS, m/z; 477 [M + H]+
515 ##STR00533## --Ac 1-[(3S)-3-{[(3S- 3-({3-[7-fluoro-3-
(propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}methyl)pyrrolidin- 1-yl]methyl}pyrrolidin- 1-yl]ethanone
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.49 (6H, d, J = 7.1 Hz),
1.52-1.78 (2H, m), 1.92-2.21 (5H, m), 2.29-2.83 (8H, m), 3.01-3.19
(3H, m), 3.30-3.73 (4H, m), 7.17-7.27 (2H, m), 7.55-7.61 (1H, m).
LC-MS, m/z; 455 [M + H]+ 516 --Ms 7-fluoro-1-(5- {[(3S)-1-{[(3S)-1-
(methylsulfonyl) pyrrolidin-3- yl]methyl}pyrrolidin- 3-yl]methyl}-
1,2,4-oxadiazol-3- yl)-3-(propan-2- yl)-1H-indazole .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.50 (6H, d, J = 7.1 Hz), 1.57-1.75 (3H, m),
2.03-2.20 (2H, m), 2.38-2.85 (10H, m), 3.03-3.11 (3H, m), 3.27-3.54
(4H, m), 7.19-7.29 (2H, m), 7.56-7.63 (1H, m). LC-MS, m/z; 491 [M +
H]+ 517 ##STR00534## --Ac 1-[(3R)-3-{[(3S)- 3-({3-[7-fluoro-3-
(propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}methyl)pyrrolidin- 1-yl]methyl}pyrrolidin- 1-yl]ethanone
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.44- 1.80 (8H, m), 1.95-2.23
(5H, m), 2.29-2.86 (8H, m), 3.02-3.21 (3H, m), 3.31-3.74 (4H, m),
7.18-7.28 (2H, m), 7.56-7.62 (1H, m). LC-MS, m/z; 455 [M + H]+ 518
##STR00535## --Ms 7-fluoro-1-(5- {[(3S)-1-{[(3R)-1-
(methylsulfonyl) pyrrolidin-3- yl]methyl}pyrrolidin- 3-yl]methyl}-
1,2,4-oxadiazol-3- yl)-3-(propan-2- yl)-1H-indazole .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.50 (6H, d, J = 7.0 Hz), 1.55-1.77 (2H, m),
1.99-2.24 (2H, m), 2.36-2.80 (8H, m), 2.82 (3H, s), 3.01-3.13 (3H,
m), 3.24-3.56 (4H, m), 7.18-7.30 (2H, m), 7.56-7.63 (1H, m). LC-MS,
m/z; 491 [M + H]+
Preparations of Examples 519 to 528
##STR00536##
[0905] Wherein HX is hydrochloric acid or trifluoroacetic acid.
[0906] The compounds in the following table (i.e. Examples 519 to
528) were prepared in the same manner as in Example 242 or the 2 N
sodium hydroxide aqueous solution was replaced with
methylamine/methanol solution, provided that the
4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-1,4-
'-bipiperidine dihydrochloride of Example 242 was replaced with the
corresponding starting compound. Each of the hydrochlorides in the
following table was obtained by dissolving the resultant compound
in methylene chloride and then treating with 1N HCl/diethyl ether
solution. In order to obtain each of the trifluoroacetates, the
residue was isolated/purified by reverse phase HPLC.
TABLE-US-00074 TABLE 74 Ex. R.sup.3 R.sup.6 R.sup.7 Compound Name
.sup.1H-NMR/LC-MS, m/z 519 .sup.iPr H H 2-hydroxy-1-(4-{3-
3-(propan-2-yl)- 1H-indazol-1-yl]- 1,2,4-oxadiazol-5- yl}-1,4'-
bipiperidin-1'- yl)ethanone LC-MS, m/z; 453 [M + H]+ 520 .sup.iPr F
F 1-(4-{3-[6,7- difluoro-3- (propan-2-yl)-1H- indazol-1-yl]-
1,2,4-oxadiazol-5- yl}-1,4'- bipiperidin-1'- yl)-2- hydroxyethanone
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.35- 1.55 (6H, m), 1.55-1.87
(2H, m), 2.00-2.80 (7H, m), 2.90-3.15 (2H, m), 3.15-3.90 (7H, m),
4.00- 4.37 (2H, m), 4.60-4.85 (1H, m), 6.90-7.30 (1H, m), 7.42-7.60
(1H, m). A signal due to OH was not observed. LC-MS, m/z; 489 [M +
H]+ 521 ##STR00537## H F 1-(4-{3-[7-fluoro- 3-(prop-1-en-2-
yl)-1H-indazol-1- yl]-1,2,4- oxadiazol-5-yl}- 1,4'-bipiperidin-
1'-yl)-2- hydroxyethanone hydrochloride .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 1.46- 1.80 (2H, m), 2.08-2.70 (9H, m), 2.89-3.67 (8H, m),
3.81-3.95 (1H, m), 4.02-4.21 (2H, m), 4.41- 4.77 (2H, m), 5.67 (1H,
s), 6.00 (1H, s), 7.39- 7.59 (2H, m), 7.95-8.04 (1H, m),
11.09-11.28 (1H, bs). LC-MS, m/z; 469 [M + H]+ 522 ##STR00538## H H
1-{4-[3-(3-tert- butyl-1H-indazol- 1-yl)-1,2,4- oxadiazol-5-yl]-
1,4'-bipiperidin- 1'-yl}-2- hydroxyethanone .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.42- 1.67 (11H, m), 1.82-2.26 (7H, m),
2.33-2.46 (2H, m), 2.53-2.82 (2H, m), 2.91-3.14 (4H, m), 3.57 (1H,
d, J = 13.8 Hz), 4.17 (2H, s), 4.63 (1H, d, J = 13.8 Hz), 7.24-
7.35 (1H, m), 7.53 (1H, t, J = 7.8 Hz), 7.94 (1H, d, J = 8.3 Hz),
8.32 (1H, d, J = 8.4 Hz). LC-MS, m/z; 467 [M + H]+ 523 ##STR00539##
H F 1-{4-[3-(3- cyclopropyl-7- fluoro-1H-indazol- 1-yl)-1,2,4-
oxadiazol-5-yl]- 1,4'-bipiperidin- 1'-yl}-2- hydroxyethanone
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.07- 1.18 (2H, m), 1.19-1.27
(2H, m), 1.40-1.58 (2H, m), 1.83-2.11 (4H, m), 2.13-2.47 (5H, m),
2.52- 2.65 (1H, m), 2.67-2.80 (1H, m), 2.91-3.10 (4H, m), 3.50-3.75
(2H, m), 4.16 (2H, s), 4.55-4.69 (1H, m), 7.18-7.29 (2H, m),
7.55-7.62 (1H, m). LC-MS, m/z; 469 [M + H]+ 524 .sup.nPr H F
1-{4-[3-(7-fluoro- 3-propyl-1H- indazol-1-yl)- 1,2,4-oxadiazol-5-
yl]-1,4'- bipiperidin-1'- yl}-2- hydroxyethanone .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.04 (3H, t, J = 7.3 Hz), 1.41-1.59 (2H, m),
1.81- 1.95 (4H, m), 1.96-2.12 (2H, m), 2.14-2.26 (2H, m), 2.32-2.47
(2H, m), 2.53-2.65 (1H, m), 2.67- 2.80 (1H, m), 2.92-3.11 (6H, m),
3.50-3.76 (2H, m), 4.16 (2H, s), 4.56- 4.68 (1H, m), 7.19-7.30 (2H,
m), 7.50-7.57 (1H, m). LC-MS, m/z; 471 [M + H]+ 525 Me H F
1-{4-[3-(7-fluoro- 3-methyl-1H- indazol-1-yl)- 1,2,4-oxadiazol-5-
yl]-1,4'- bipiperidin-1'- yl}-2- hydroxyethanone .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.40- 1.59 (2H, m), 1.84-2.12 (4H, m),
2.15-2.26 (2H, m), 2.34-2.47 (2H, m), 2.53-2.80 (5H, m), 2.92- 3.11
(4H, m), 3.50-3.74 (2H, m), 4.16 (2H, s), 4.56-4.68 (1H, m), 7.21-
7.31 (2H, m), 7.48-7.53 (1H, m). LC-MS, m/z; 443 [M + H]+ 526
##STR00540## H F 1-(4-{3-[7-fluoro- 3-(2- methylpropyl)-1H-
indazol-1-yl]- 1,2,4-oxadiazol-5- yl}-1,4'- bipiperidin-1'- yl)-2-
hydroxyethanone .sup.1H-NMR (CDCl.sub.3) .delta.: 1.00 (6H, d, J =
6.8 Hz), 1.41-1.59 (2H, m), 1.82- 2.11 (4H, m), 2.14-2.32 (3H, m),
2.33-2.47 (2H, m), 2.53-2.81 (2H, m), 2.87-3.12 (6H, m), 3.50- 3.76
(2H, m), 4.16 (2H, s), 4.57-4.68 (1H, m), 7.19-7.29 (2H, m), 7.49-
7.55 (1H, m). LC-MS, m/z; 485 [M + H]+ 527 ##STR00541## H F
1-{4-[3-(3- cyclobutyl-7- fluoro-1H-indazol- 1-yl)-1,2,4-
oxadiazol-5-yl]- 1,4'-bipiperidin- 1'-yl}-2- hydroxyethanone
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.41- 1.60 (2H, m), 1.85-2.29
(8H, m), 2.34-2.81 (8H, m), 2.91-3.14 (4H, m), 3.43-3.82 (2H, m),
3.91- 4.05 (1H, m), 4.16 (2H, s), 4.57-4.69 (1H, m), 7.17-7.29 (2H,
m), 7.49- 7.56 (1H, m). LC-MS, m/z; 483 [M + H]+ 528 ##STR00542## H
F 1-(4-{3-[3-(butan- 2-yl)-7-fluoro-1H- indazol-1-yl]-
1,2,4-oxadiazol-5- yl}-1,4'- bipiperidin-1'- yl)-2- hydroxyethanone
.sup.1H-NMR (CDCl.sub.3) .delta.: 0.93 (3H, t, J = 7.4 Hz),
1.42-1.57 (4H, m), 1.76- 2.10 (6H, m), 2.15-2.24 (2H, m), 2.33-2.44
(2H, m), 2.54-2.64 (1H, m), 2.69-2.82 (2H, m), 2.93- 3.10 (4H, m),
3.19-3.30 (1H, m), 3.51-3.71 (2H, m), 4.16 (2H, s), 4.58- 4.67 (1H,
m), 7.18-7.28 (2H, m), 7.55-7.60 (1H, m). LC-MS, m/z; 485 [M +
H]+
Preparations of Examples 529 to 538
##STR00543##
[0907] Wherein HX is hydrochloric acid or trifluoroacetic acid, and
(R.sup.12-1) means each cyclic amino structure shown in the
following table. The hydroxyacetyl group is attached to the
nitrogen atom in the cyclic amine of (R.sup.12-1).
[0908] The compounds in the following table (i.e. Examples 529 to
538) were prepared in the same manner as in Example 242 or the 2 N
sodium hydroxide aqueous solution was replaced with
methylamine/methanol, provided that the
4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-1,4-
'-bipiperidine dihydrochloride was replaced with the corresponding
starting compound. Each of the hydrochlorides in the following
table was obtained by dissolving the resultant compound in
methylene chloride and then treating with 1N HCl/diethyl ether
solution.
TABLE-US-00075 TABLE 75 Ex. R.sup.3 (R.sup.12-1) Compound Name
.sup.1H-NMR/LC-MS, m/z 529 .sup.iPr ##STR00544##
1-{(2R)-2-[(4-{3-[7- fluoro-3-(propan-2- yl)-1H-indazol-1-
yl]-1,2,4-oxadiazol- 5-yl}piperidin-1- yl)methyl]pyrrolidin-
1-yl}-2- hydroxyethanone hydrochloride .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 1.41 (6H, d, J = 7.0 Hz), 1.80-2.48 (7H, m), 3.04-4.12
(14H, m), 4.36- 4.58 (1H, m), 7.34-7.55 (2H, m), 7.84 (1H, d, J =
7.7 Hz), 10.14- 10.51 (1H, br m). LC-MS, m/z; 471 [M + H]+ 530
.sup.iPr ##STR00545## 1-(4-{3-[7-fluoro-3- (propan-2-yl)-1H-
indazol-1-yl]-1,2,4- oxadiazol-5-yl}-3'- methyl-1,4'-
bipiperidin-1'-yl)- 2-hydroxyethanone .sup.1H-NMR (CDCl.sub.3)
.delta.: 0.91 (3H, t, J = 7.4 Hz), 1.44-1.66 (2H, m), 1.51 (6H, d,
J = 7.1 Hz), 1.79-1.89 (1H, m), 1.97-2.33 (7H, m), 2.55-3.16 (5H,
m), 3.27-3.60 (2H, m), 3.61-3.70 (1H, m), 4.06-4.29 (2H, m),
4.48-4.73 (1H, m), 7.18-7.29 (2H, m), 7.55-7.63 (1H, m). LC-MS,
m/z; 485 [M + H]+ 531 .sup.iPr ##STR00546## 1-(4-{3-[7-fluoro-3-
(propan-2-yl)-1H- indazol-1-yl]-1,2,4- oxadiazol-5-yl}-3',
3'-dimethyl-1,4'- bipiperidin-1'-yl)- 2-hydroxyethanone .sup.1H-NMR
(CDCl.sub.3) .delta.: 0.85-0.92 (3H, m), 0.97-1.06 (3H, m), 1.50
(6H, t, J = 3.6 Hz), 1.68-1.80 (2H, m), 1.90-2.43 (6H, m),
2.52-3.71 (9H, m), 4.04-4.80 (3H, m), 7.16-7.30 (2H, m), 7.55-7.62
(1H, m). LC-MS, m/z; 499 [M + H]+ 532 and 533 .sup.iPr ##STR00547##
1-[(3-endo)-3-(4-{3- [7-fluoro-3-(propan- 2-yl)-1H-indazol-1-
yl]-1,2,4-oxadiazol- 5-yl}piperidin-1- yl)-8- azabicyclo[3.2.1]oct-
8-yl]-2- hydroxyethanone and .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50
(6H, d, J = 7.1 Hz), 1.81-2.27 (14H, m), 2.33- 2.41 (1H, m),
2.98-3.25 (3H, m), 3.42-3.58 (2H, m), 3.88-3.95 (1H, m), 4.11 (2H,
dd, J = 28.7, 14.8 Hz), 1-[(3-exo)-3-(4-{3- [7-fluoro-3-(propan-
2-yl)-1H-indazol-1- yl]-1,2,4-oxadiazol- 5-yl}piperidin-1- yl)-8-
azabicyclo[3.2.1]oct- 8-yl]-2- hydroxyethanone 4.62-4.70 (1H, m),
7.18-7.29 (2H, m), 7.56-7.62 (1H, m). LC-MS, m/z; 497 [M + H]+ and
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (6H, d, J = 6.8 Hz),
1.53-1.67 (2H, m), 1.67-2.08 (8H, m), 2.13-2.23 (2H, m), 2.26-2.37
(2H, m), 2.83-3.09 (4H, m), 3.42-3.58 (2H, m), 3.99-4.21 (3H, m),
4.75-4.82 (1H, m), 7.18-7.30 (2H, m), 7.56-7.62 (1H, m). LC-MS,
m/z; 497 [M + H]+ 534 .sup.iPr ##STR00548## 1-[(8-anti)-8-(4-(3-
[7-fluoro-3-(propan- 2-yl)-1H-indazol-1- yl]-1,2,4-oxadiazol-
5-yl}piperidin-1- yl)-3- azabicyclo[3.2.1]oct- 3-yl]-2-
hydroxyethanone .sup.1H-NMR (CDCl.sub.3) .delta.: 1.42-1.59 (7H,
m), 1.73-1.88 (2H, m), 1.99-2.37 (10H, m), 2.90 (1H, d, J = 11.0
Hz), 2.97- 3.16 (3H, m), 3.26 (1H, d, J = 12.3 Hz), 3.41-3.59 (2H,
m), 3.78 (1H, t, J = 4.3 Hz), 3.93-4.10 (2H, m), 4.18-4.29 (1H, m),
7.17-7.30 (2H, m), 7.55-7.63 (1H, m). LC-MS, m/z; 497 [M + H]+ 535
and 536 .sup.iPr ##STR00549## 1-[(9-anti)-9-(4-{3-
[7-fluoro-3-(propan- 2-yl)-1H-indazol-1- yl]-1,2,4-oxadiazol-
5-yl}piperidin-1- yl)-3- azabicyclo[3.3.1]non- 3-yl]-2-
hydroxyethanone and 1-[(9-syn)-9-(4-{3- [7-fluoro-3-(propan-
2-yl)-1H-indazol-1- yl]-1,2,4-oxadiazol- 5-yl}piperidin-1- yl)-3-
azabicyclo[3.3.1]non- 3-yl]-2- hydroxyethanone .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.38-1.61 (9H, m), 1.89-2.28 (12H, m),
2.94-3.31 (5H, m), 3.42-3.62 (2H, m), 3.69-3.80 (1H, m), 4.08-4.29
(2H, m), 4.60-4.69 (1H, m), 7.18-7.30 (2H, m), 7.57-7.63 (1H, m).
LC-MS, m/z; 511 [M + H]+ And LC-MS, m/z; 511 [M + H]+ 537 .sup.iPr
##STR00550## 1-(4-{3-[7-fluoro-3- (propan-2-yl)-1H-
indazol-1-yl]-1,2,4- oxadiazol-5-yl}-4'- methyl-1,4'-
bipiperidin-1'-yl)- 2-hydroxyethanone .sup.1H-NMR (CDCl.sub.3)
.delta.: 0.96 (3H, s), 1.32-1.44 (2H, m), 1.47-1.58 (6H, m),
1.89-2.09 (4H, m), 2.13-2.37 (4H, m), 2.93-3.19 (4H, m), 3.22-3.55
(3H, m), 3.73 (1H, t, J = 4.2 Hz), 4.00-4.23 (3H, m), 7.17-7.30
(2H, m), 7.55-7.63 (1H, m). LC-MS, m/z; 485 [M + H]+ 538 Et
##STR00551## 1-{4-[3-(3-ethyl-7- fluoro-1H-indazol-1-
yl)-1,2,4-oxadiazol- 5-yl]-4'-methyl- 1,4'-bipiperidin-1'- yl}-2-
hydroxyethanone .sup.1H-NMR (CDCl.sub.3) .delta.: 0.96 (3H, s),
1.30-1.51 (5H, m), 1.87-2.08 (4H, m), 2.11-2.37 (4H, m), 2.88-3.15
(6H, m), 3.19-3.41 (2H, m), 3.71 (1H, t, J = 4.2 Hz), 3.98-4.08
(1H, m), 4.10-4.21 (2H, m), 7.18-7.29 (2H, m), 7.48-7.54 (1H, m).
LC-MS, m/z; 471 [M + H]+
Preparations of Examples 539 to 544
##STR00552##
[0909] Wherein (R.sup.12-1) means each cyclic amino structure shown
in the following table. The hydroxyacetyl group is attached to the
nitrogen atom in the cyclic amine of (R.sup.12-1).
[0910] The compounds in the following table (i.e. Examples 539 to
544) were prepared in the same manner as in Example 242 or the 2 N
sodium hydroxide aqueous solution was replaced with
methylamine/methanol, provided that the
4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-1,4-
'-bipiperidine dihydrochloride was replaced with the corresponding
starting compound.
TABLE-US-00076 TABLE 76 Ex. (R.sup.12-1) Compound Name
.sup.1H-NMR/LC-MS, m/z 539 ##STR00553## 1-{4-[(3R)-3-({3-[7-
fluoro-3-(propan-2- yl)-1H-indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}methyl)pyrrolidin- 1-yl]piperidin-1-yl}- 2-hydroxyethanone
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.40- 1.58 (8H, m), 1.59-1.74
(1H, m), 1.81-1.95 (2H, m), 2.08-3.15 (11H, m), 3.40-3.56 (3H, m),
4.14 (2H, s), 4.20-4.38 (1H, m), 7.18-7.30 (2H, m), 7.55-7.64 (1H,
m). LC-MS, m/z; 471 [M + H]+ 540 ##STR00554## 1-[(2S)-2-{[(3R)-3-
({3-[7-fluoro-3- (propan-2-yl)-1H- indazol-1-yl]-1,2,4-
oxadiazol-5- yl}methyl)pyrrolidin- 1- yl]methyl}pyrrolidin-
1-yl]-2- hydroxyethanone .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50
(6H, d, J = 7.2 Hz), 1.59-1.79 (1H, m), 1.84- 2.26 (5H, m),
2.46-3.56 (14H, m), 3.99-4.35 (2H, m), 7.18-7.30 (2H, m), 7.55-7.63
(1H, m). LC-MS, m/z; 471 [M + H]+ 541 ##STR00555##
1-[(2R)-2-{[(3R)-3- ({3-[7-fluoro-3- (propan-2-yl)-1H-
indazol-1-yl]-1,2,4- oxadiazol-5- yl}methyl)pyrrolidin- 1-
yl]methyl}pyrrolidin- 1-yl]-2- hydroxyethanone .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.50 (6H, d, J = 7.0 Hz), 1.56-1.73 (1H, m),
1.81- 2.24 (5H, m), 2.32-3.38 (12H, m), 3.41-3.56 (2H, m),
3.99-4.35 (2H, m), 7.18-7.30 (2H, m), 7.55- 7.63 (1H, m). LC-MS,
m/z; 471 [M + H]+ 542 ##STR00556## 1-(3-{[(3R)-3-({3-[7-
fluoro-3-(propan-2- yl)-1H-indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}methyl)pyrrolidin- 1-yl]methyl}azetidin- 1-yl)-2-
hydroxyethanone .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (6H, d, J =
7.1 Hz), 1.57-1.75 (2H, m), 2.08- 2.21 (1H, m), 2.38-2.92 (8H, m),
3.06 (2H, d, J = 6.8 Hz), 3.41-3.55 (1H, m), 3.67-3.79 (2H, m),
3.94 (2H, br s), 4.05- 4.22 (2H, m), 7.20-7.29 (2H, m), 7.57-7.63
(1H, m). LC-MS, m/z; 457 [M + H]+ 543 ##STR00557##
1-[(3S)-3-{[(3R)-3- ({3-[7-fluoro-3- (propan-2-yl)-1H-
indazol-1-yl]-1,2,4- oxadiazol-5- yl}methyl)pyrrolidin- 1-
yl]methyl}pyrrolidin- 1-yl]-2- hydroxyethanone .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.50 (6H, d, J = 7.1 Hz), 1.53-1.82 (2H, m),
1.99- 2.21 (2H, m), 2.32-2.85 (9H, m), 3.07 (2H, d, J = 7.1 Hz),
3.16-3.54 (4H, m), 3.63-3.80 (1H, m), 4.07 (2H, br s), 7.18- 7.29
(2H, m), 7.56-7.63 (1H, m). LC-MS, m/z; 471 [M + H]+ 544
##STR00558## 1-[(3R)-3-{[(3R)-3- ({3-[7-fluoro-3- (propan-2-yl)-1H-
indazol-1-yl]-1,2,4- oxadiazol-5- yl}methyl)pyrrolidin- 1-
yl]methyl}pyrrolidin- 1-yl]-2- hydroxyethanone .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.50 (6H, d, J = 7.1 Hz), 1.54-1.82 (2H, m),
1.99- 2.22 (2H, m), 2.33-2.85 (9H, m), 3.00-3.11 (2H, m), 3.17-3.53
(4H, m), 3.62-3.81 (1H, m), 4.01- 4.13 (2H, m), 7.19-7.29 (2H, m),
7.56-7.62 (1H, m). LC-MS, m/z; 471 [M + H]+
Preparations of Examples 545 to 550
##STR00559##
[0911] Wherein (R.sup.12-1) means each cyclic amino structure shown
in the following table. The hydroxyacetyl group is attached to the
nitrogen atom in the cyclic amine of (R.sup.12-1).
[0912] The compounds in the following table (i.e. Examples 545 to
550) were prepared in the same manner as in Example 242 or the 2 N
sodium hydroxide aqueous solution was replaced with
methylamine/methanol, provided that the
4-[(3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl]-1,-
4'-bipiperidine dihydrochloride was replaced with the corresponding
starting compound.
TABLE-US-00077 TABLE 77 Ex. (R.sup.12-1) Compound Name
.sup.1H-NMR/LC-MS, m/z 545 ##STR00560## 1-{4-[(3S)-3-({3-[7-
fluoro-3-(propan-2- yl)-1H-indazol-1- yl]-1,2,4-oxadiazol- 5-
yl}methyl)pyrrolidin- 1-yl]piperidin-1- yl}-2- hydroxyethanone
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.40- 1.58 (8H, m), 1.59-1.74
(1H, m), 1.81-1.95 (2H, m), 2.08-3.15 (11H, m), 3.40-3.56 (3H, m),
4.14 (2H, s), 4.20-4.38 (1H, m), 7.18-7.30 (2H, m), 7.55-7.64 (1H,
m). LC-MS, m/z; 471 [M + H]+ 546 ##STR00561## 1-[(2S)-2-{[(3S)-3-
({3-[7-fluoro-3- (propan-2-yl)-1H- indazol-1-yl]-1,2,4-
oxadiazol-5- yl}methyl)pyrrolidin- 1- yl]methyl}pyrrolidin-
1-yl]-2- hydroxyethanone .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50
(6H, d, J = 7.0 Hz), 1.56-1.73 (1H, m), 1.81- 2.24 (5H, m),
2.32-3.38 (12H, m), 3.41-3.56 (2H, m), 3.99-4.35 (2H, m), 7.18-7.30
(2H, m), 7.55- 7.63 (1H, m). LC-MS, m/z; 471 [M + H]+ 547
##STR00562## 1-[(2R)-2-{[(3S)-3- ({3-[7-fluoro-3- (propan-2-yl)-1H-
indazol-1-yl]-1,2,4- oxadiazol-5- yl}methyl)pyrrolidin- 1-
yl]methyl}pyrrolidin- 1-yl]-2- hydroxyethanone .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.50 (6H, d, J = 7.2 Hz), 1.59-1.79 (1H, m),
1.84- 2.26 (5H, m), 2.46-3.56 (14H, m), 3.99-4.35 (2H, m),
7.18-7.30 (2H, m), 7.55-7.63 (1H, m). LC-MS, m/z; 471 [M + H]+ 548
##STR00563## 1-(3-{[(3S)-3-({3- [7-fluoro-3-(propan-
2-yl)-1H-indazol-1- yl]-1,2,4-oxadiazol- 5- yl}methyl)pyrrolidin-
1- yl]methyl}azetidin- 1-yl)-2- hydroxyethanone .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.50 (6H, d, J = 7.1 Hz), 1.57-1.75 (2H, m),
2.08- 2.21 (1H, m), 2.38-2.92 (8H, m), 3.06 (2H, d, J = 6.8 Hz),
3.41-3.55 (1H, m), 3.67-3.79 (2H, m), 3.94 (2H, br s), 4.05- 4.22
(2H, m), 7.20-7.29 (2H, m), 7.57-7.63 (1H, m). LC-MS, m/z; 457 [M +
H]+ 549 ##STR00564## 1-[(3S)-3-{[(3S)-3- ({3-[7-fluoro-3-
(propan-2-yl)-1H- indazol-1-yl]-1,2,4- oxadiazol-5-
yl}methyl)pyrrolidin- 1- yl]methyl}pyrrolidin- 1-yl]-2-
hydroxyethanone .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (6H, d, J =
7.1 Hz), 1.54-1.82 (2H, m), 1.99- 2.22 (2H, m), 2.33-2.85 (9H, m),
3.00-3.11 (2H, m), 3.17-3.53 (4H, m), 3.62-3.81 (1H, m), 4.01- 4.13
(2H, m), 7.19-7.29 (2H, m), 7.56-7.62 (1H, m). LC-MS, m/z; 471 [M +
H]+ 550 ##STR00565## 1-[(3R)-3-{[(3S)-3- ({3-[7-fluoro-3-
(propan-2-yl)-1H- indazol-1-yl]-1,2,4- oxadiazol-5-
yl}methyl)pyrrolidin- 1- yl]methyl}pyrrolidin- 1-yl]-2-
hydroxyethanone .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (6H, d, J =
7.1 Hz), 1.53-1.82 (2H, m), 1.99- 2.21 (2H, m), 2.32-2.85 (9H, m),
3.07 (2H, d, J = 7.1 Hz), 3.16-3.54 (4H, m), 3.63-3.80 (1H, m),
4.07 (2H, br s), 7.18- 7.29 (2H, m), 7.56-7.63 (1H, m). LC-MS, m/z;
471 [M + H]+
Example 551
Preparation of
1-(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}--
4-hydroxy-1,4'-bipiperidin-1'-yl)-2-hydroxyethanone
##STR00566##
[0914] The title compound was prepared in the same manner as in
Example 242 except that the
4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-1,4-
'-bipiperidine dihydrochloride was replaced with
4-{3-[fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-1,4'--
bipiperidin-4-ol dihydrochloride and the 2 N sodium hydroxide
aqueous solution was replaced with methylamine/methanol.
[0915] LC-MS, m/z; 487 [M+H]+
Example 552
Preparation of
1-(4-{3-[7-fluoro-6-hydroxy-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadia-
zol-5-yl}-1,4'-bipiperidin-1'-yl)-2-hydroxyethanone
##STR00567##
[0917] (1) To a mixture of
4-{3-[7-fluoro-6-methoxy-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-
-5-yl}-1,4'-bipiperidine bis(trifluoroacetate) (250 mg),
dichloromethane (5.0 ml) and saturated sodium bicarbonate aqueous
solution (5.0 ml) was added dropwise acetoxyacetyl chloride (60
.mu.l) at ice temperature, and the mixture was stirred for 30
minutes. To the solution was added saturated sodium bicarbonate,
and the mixture was extracted with ethyl acetate. The organic layer
was washed with water, dried, evaporated under reduced pressure,
and the residue was purified by silica-gel chromatography (column;
Hi-Flash.TM., developing solvent: chloroform/methanol=20:1) to give
2-(4-{3-[7-fluoro-6-methoxy-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadia-
zol-5-yl}-1,4'-bipiperidin-1'-yl)-2-oxoethyl acetate (207 mg).
[0918] (2) The
2-(4-{3-[7-fluoro-6-methoxy-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadia-
zol-5-yl}-1,4'-bipiperidin-1'-yl)-2-oxoethyl acetate (162 mg) was
dissolved in dichloromethane (15 ml). To the solution was added 1N
BBr.sub.3 (in dichloromethane, 3.59 ml), and the mixed solution was
stirred at room temperature overnight and then cooled at ice
temperature. To the reaction solution was added saturated sodium
bicarbonate aqueous solution, and the mixture was extracted with
chloroform. The organic layer was dried, concentrated, and the
residue was purified by silica-gel chromatography (column;
Hi-Flash.TM., developing solvent: chloroform/methanol=10:1) to give
the title compound (112 mg).
[0919] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.39-1.59 (9H, m),
1.83-2.25 (6H, m), 2.32-2.48 (2H, m), 2.55-2.78 (2H, m), 2.91-3.08
(4H, m), 3.35-3.44 (1H, m), 3.56 (1H, d, J=13.8 Hz), 4.16 (2H, s),
4.63 (1H, d, J=13.0 Hz), 5.30 (1H, s), 6.99 (1H, dd, J=8.6, 6.8
Hz), 7.41 (1H, dd, J=8.6, 0.7 Hz).
[0920] LC-MS, m/z; 487 [M+H]+
Example 553
Preparation of
1-(4-{3-[7-fluoro-4-hydroxy-3-(propan-2-yl)-1,1'-indazol-1-yl]-1,2,4-oxad-
iazol-5-yl}-1,4'-bipiperidin-1'-yl)-2-hydroxyethanone
##STR00568##
[0922] The title compound was prepared in the same manner as in
Example 552 except that the
4-{3-[7-fluoro-6-methoxy-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-
-5-yl}-1,4'-bipiperidine bis(trifluoroacetate) was replaced with
4-{3-[7-fluoro-4-methoxy-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-
-5-yl}-1,4'-bipiperidine bis(trifluoroacetate).
[0923] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12-1.40 (9H, m),
1.59-1.77 (4H, m), 1.93-2.06 (2H, m), 2.16-2.33 (2H, m), 2.37-2.58
(1H, m), 2.72-2.90 (3H, m), 2.97-3.10 (1H, m), 3.46-3.68 (2H, m),
3.91-4.06 (2H, m), 4.21-4.44 (2H, m), 5.65-5.69 (1H, m), 6.49 (1H,
dd, J=8.5, 2.8 Hz), 7.10 (1H, dd, J=11.4, 8.4 Hz).
[0924] LC-MS, m/z; 487 [M+H]+
Example 554
Preparation of
1-(4-{3-[7-fluoro-6-hydroxy-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadia-
zol-5-yl}-1,4'-bipiperidin-1'-yl)ethanone
##STR00569##
[0926] The title compound was prepared in the same manner as in
Example 552 (2) except that the intermediate of Example 552 was
replaced with
1-(4-{3-[7-fluoro-6-methoxy-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadia-
zol-5-yl}-1,4'-bipiperidin-1'-yl)ethanone.
[0927] LC-MS, m/z; 471 [M+H]+
Example 555
Preparation of
1-(4-{3-[7-fluoro-4-hydroxy-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadia-
zol-5-yl}-1,4'-bipiperidin-1'-yl)ethanone
##STR00570##
[0929] The title compound was prepared in the same manner as in
Example 552 (2) except that the intermediate of Example 552 was
replaced with
1-(4-{3-[7-fluoro-4-methoxy-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadia-
zol-5-yl}-1,4'-bipiperidin-1'-yl)ethanone.
[0930] LC-MS, m/z; 471 [M+H]+
Example 556
Preparation of ethyl
4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-3'--
methoxy-1,4'-bipiperidine-1'-carboxylate
##STR00571##
[0932] The title compound was prepared in the same manner as in
Example 028 except that the
3-ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and
(S)-(-)-1-tert-butoxycarbonyl-2-pyrrolidinecarbaldehyde were
replaced with
7-fluoro-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-3-(propan-2-yl)-
-1H-indazole trifluoroacetate and ethyl
3-methoxy-4-oxopiperidine-1-carboxylate, respectively, and titanium
tetraisopropoxide was added to the reaction.
[0933] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.17-1.32 (3H, m), 1.50
(6H, d, J=7.0 Hz), 1.57-1.71 (1H, m), 1.85-2.23 (4H, m), 2.31-3.21
(8H, m), 3.25-3.67 (6H, m), 3.97-4.61 (4H, m), 7.15-7.28 (2H, m),
7.53-7.61 (1H, m).
[0934] LC-MS, m/z; 515 [M+H]+
Example 557
Preparation of potassium
(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-1,-
4'-bipiperidin-1'-yl)(oxo)acetate
##STR00572##
[0936] (1)
4-{3-[7-Fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-
-5-yl}-1,4'-bipiperidine dihydrochloride (500 mg) was dissolved in
dichloromethane (5.0 ml), and the solution was ice-cooled.
Diisopropylethylamine (578 .mu.l) and ethyloxalyl chloride (126
.mu.l) were added thereto, and the mixture was stirred at the same
temperature for 30 minutes. The reaction solution was diluted with
chloroform and washed with water. The organic layer was dried, and
the solvent was removed under reduced pressure.
[0937] (2) The residue was dissolved in methanol (5.0 ml),
potassium hydroxide (58 mg) and water (1.0 ml) were added thereto,
and the mixture was stirred at room temperature for 3 hours. The
solvent was removed under reduced pressure, and the residue was
purified by silica-gel chromatography (column; Hi-Flash.TM.
Octadecyl, developing solvent: acetonitrile/water=1:1) to give the
title compound (415 mg).
[0938] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.11-1.46 (8H, m),
1.61-1.88 (4H, m), 2.02-2.16 (2H, m), 2.29-2.60 (4H, m), 2.73-2.97
(3H, m), 3.07-3.21 (1H, m), 3.42-3.55 (1H, m), 3.68-3.80 (1H, m),
4.19-4.30 (1H, m), 7.30-7.49 (2H, m), 7.81 (1H, d, J=7.7 Hz).
[0939] LC-MS, m/z; 485 [M+H]+
Preparations of Examples 558 to 559
##STR00573##
[0941] The compounds in the following table (i.e. Examples 558 to
559) were prepared in the same manner as in Example 242 except that
the
4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-1,4-
'-bipiperidine dihydrochloride and acetoxyacetyl chloride were
replaced with the corresponding starting compound and
(S)-(-)-2-acetoxypropionyl chloride, respectively, and the 2 N
sodium hydroxide aqueous solution was replaced with
methylamine/methanol.
TABLE-US-00078 TABLE 78 .sup.1H-NMR/ Ex. R.sup.3 Compound Name
LC-MS, m/z 558 .sup.iPr (2S)-1-(4-{3-[7- .sup.1H-NMR (CDCl.sub.3)
.delta.: fluoro-3-(propan- 0.94 (3H, d, J = 5.5 Hz),
2-yl)-1H-indazol-1-yl]-1,2,4- 1.26-1.42 (5H, m), 1.48 (6H,
oxadiazol-5-yl}-4'- d, J = 7.0 Hz), methyl-1,4'- 1.85-2.07 (4H, m),
bipiperidin-1'-yl)-2- 2.11-2.36 (4H, m), hydroxypropan-1-one
2.90-3.09 (3H, m), 3.17-3.52 (4H, m), 3.89-4.13 (2H, m), 4.43 (1H,
dd, J = 13.8, 7.1 Hz), 7.15-7.25 (2H, m), 7.54-7.59 (1H, m). LC-MS,
m/z; 499 [M + H]+ 559.sup.1) Et (2S)-1-{4-[3-(3- .sup.1H-NMR
(DMSO-d.sub.6) .delta.: ethyl-7-fluoro- 1.15 (3H, s),
1H-indazol-1-yl)- 1.28-1.40 (6H, m), 1,2,4-oxadiazol- 1.80-2.03
(3H, m), 5-yl]-4'-methyl-1,4'- 2.23-2.39 (4H, m), bipiperidin-
2.60-2.76 (1H, m), 1'-yl}-2-hydroxypropan-1-one 2.95-3.18 (4H, m),
hydrochloride 3.23-3.41 (3H, m), 3.46-3.72 (3H, m), 3.96-4.11 (1H,
m), 4.30-4.48 (2H, m), 7.29-7.49 (2H, m), 7.70-7.79 (1H, m),
10.08-10.39 (1H, m). LC-MS, m/z; 485 [M + H]+ .sup.1)The crude
product was treated with 1N HCl/diethyl ether solution to obtain
the desired compound.
Example 560
Preparation of
7-fluoro-1-[5-(4-fluoropiperidin-4-yl)-1,2,4-oxadiazol-3-yl]-3-(propan-2--
yl)-1H-indazole trifluoroacetate
##STR00574##
[0943] The title compound was prepared in the same manner as in
Example 001 except that the tert-butyl
4-[3-(3-ethyl-6-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidine-1-
-carboxylate was replaced with tert-butyl
4-fluoro-4-(3-(7-fluoro-3-isopropyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl-
)piperidine-1-carboxylate.
[0944] LC-MS, m/z; 348 [M+H]+
Example 561
Preparation of
1-(4-fluoro-4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiaz-
ol-5-yl}-1,4'-bipiperidin-1'-yl)ethanone
##STR00575##
[0946] The title compound was prepared in the same manner as in
Example 028 except that the
3-ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and
(S)-(-)-1-tert-butoxycarbonyl-2-pyrrolidinecarbaldehyde were
replaced with
7-fluoro-1-[5-(4-fluoropiperidin-4-yl)-1,2,4-oxadiazol-3-yl]-3-(prop-
an-2-yl)-1H-indazole trifluoroacetate and 1-acetylpiperidin-4-one,
respectively.
[0947] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.39-1.57 (8H, m),
1.80-1.93 (2H, m), 2.10 (3H, s), 2.28-2.45 (4H, m), 2.51-2.89 (6H,
m), 3.00-3.13 (1H, m), 3.41-3.55 (1H, m), 3.88 (1H, d, J=13.9 Hz),
4.67 (1H, d, J=13.4 Hz), 7.19-7.30 (2H, m), 7.57-7.62 (1H, m).
[0948] LC-MS, m/z; 473 [M+H]+
Preparations of Examples 562 to 565
##STR00576##
[0949] Wherein HX is hydrochloric acid or trifluoroacetic acid. HX
is absent in Example 565.
[0950] The compounds in the following table (i.e. Examples 562 to
565) were prepared in the same manner as in Example 097 except that
the
3-ethyl-6-fluoro-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and ethyl iodide were replaced with the
corresponding starting compound and butyl bromide, respectively.
Each free form of the compounds in the following table was obtained
by omitting the conversion step into hydrochloride in Example
097.
TABLE-US-00079 TABLE 79 .sup.1H-NMR/ Ex. Q Compound Name LC-MS, m/z
562 ##STR00577## 1-[5-(1- butylpiperidin- 4-yl)-1H- imidazol-2-yl]-
7-fluoro-3- (propan-2-yl)- 1H-indazole LC-MS, m/z; 384 [M + H]+ 563
##STR00578## 1-[5-(1- butylpiperidin- 4-yl)-1,3- thiazol-2-yl]-7-
fluoro-3- (propan-2-yl)- 1H-indazole .sup.1H-NMR (CDCl.sub.3)
.delta.: 0.93 (3H, t, J = 7.2 Hz), 1.26-1.41 (2H, m), 1.43- 1.58
(8H, m), 1.79-1.92 (2H, m), 1.97- 2.13 (4H, m), 2.30-2.42 (2H, m),
2.76-2.90 (1H, m), 3.03 (2H, d, J = 11.6 Hz), 3.35- 3.49 (1H, m),
7.15-7.24 (2H, m), 7.32-7.35 (1H, m), 7.49- 7.57 (1H, m). LC-MS,
m/z; 401 [M + H]+ 564 ##STR00579## 1-[2-(1- butylpiperidin-
4-yl)-1,3- thiazol-5-yl]-7- fluoro-3- (propan-2-yl)- 1H-indazole
.sup.1H-NMR (CDCl.sub.3 ) .delta.: 0.94 (3H, t, J = 7.3 Hz),
1.28-1.65 (10H, m), 1.92- 2.09 (2H, m), 2.17-2.36 (4H, m), 2.41-
2.56 (2H, m), 3.00-3.20 (3H, m), 3.35- 3.50 (1H, m), 7.07-7.17 (2H,
m), 7.51- 7.58 (1H, m), 7.75-7.79 (1H, m). LC-MS, m/z; 401 [M + H]+
565 ##STR00580## 1-[1-(1- butylpiperidin- 4-yl)-1H-
1,2,3-triazol-4- yl]-7-fluoro-3- (propan-2-yl)- 1H-indazole
.sup.1H-NMR (CDCl.sub.3) .delta.: 0.94 (3H, t, J = 7.2 Hz),
1.26-1.59 (10H, m), 2.04- 2.46 (8H, m), 3.03-3.17 (2H, m),
3.38-3.52 (1H, m), 4.51- 4.63 (1H, m), 7.05-7.16 (2H, m), 7.53-
7.59 (1H, m), 7.81 (1H, d, J = 1.5 Hz). LC-MS, m/z; 385 [M +
H]+
Example 566
Preparation of
N-{3-[(cis-3-{3-[7-fluoro-3-(propan-2-yl]-yl}cyclobutyl)amino]propyl}acet-
amide
##STR00581##
[0952] (1)
N-(cis-3-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-ox-
adiazol-5-yl}cyclobutyl)-2-nitrobenzenesulfonamide was prepared in
the same manner as in Reference Example 060 except that the
3-ethyl-6-fluoro-N-hydroxy-1H-indazole-1-carboximidamide and
3-oxocyclobutanecarboxylic acid were replaced with
7-fluoro-N'-hydroxy-3-(propan-2-yl)-1H-indazole-1-carboximidamide
and cis-3-{[(2-nitrophenyl)sulfonyl]amino}cyclobutanecarboxylic
acid.
[0953] (2) To the
N-(cis-3-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5--
yl}cyclobutyl)-2-nitrobenzenesulfonamide (200 mg),
3-(tert-butoxycarbonylamino)-1-propanol (210 mg) and
tributylphosphine (0.3 ml) in THF (1 ml) was added dropwise diethyl
azodicarboxylate (0.2 ml), and the mixture was stirred at
60.degree. C. for 5 hours. To the reaction solution was added water
(2 ml), and the mixture was extracted with ethyl acetate (2
ml.times.3). The organic layer was dried over anhydrous magnesium
sulfate, filtered, and concentrated under reduced pressure. The
residue was purified by silica-gel chromatography to give
tert-butyl
(3-{(cis-3-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol--
5-yl}cyclobutyl)[(2-nitrophenyl)sulfonyl]amino}propyl)carbamate
(170 mg).
[0954] LC-MS, m/z; 658 [M+H]+
[0955] (3) To the tert-butyl
(3-{(cis-3-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol--
5-yl}cyclobutyl) [(2-nitrophenyl)sulfonyl]amino}propyl)carbamate
(170 mg) was added 4 mol/L HCl/ethyl acetate (3 ml), and the
mixture was stirred at room temperature for 1 hour. The reaction
solution was concentrated under reduced pressure to give a
quantitative amount of
N-(3-aminopropyl)-N-(cis-3-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]--
1,2,4-oxadiazol-5-yl}cyclobutyl)-2-nitrobenzenesulfonamide
hydrochrolide.
[0956] LC-MS, m/z; 558 [M+H]+
[0957] (4) To the
N-(3-aminopropyl)-N-(cis-3-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]--
1,2,4-oxadiazol-5-yl}cyclobutyl)-2-nitrobenzenesulfonamide
hydrochrolide (60 mg) and triethylamine (30 .mu.l) in
dichloromethane (1 ml) was added acetyl chloride (9 .mu.l), and the
mixture was stirred at room temperature for 1 hour. The reaction
solution was purified by silica-gel chromatography to give
N-(3-{(cis-3-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazo-
l-5-yl}cyclobutyl) [(2-nitrophenyl)sulfonyl]amino}propyl)acetamide
(56 mg).
[0958] (5) To the
N-(3-{(cis-3-{3-[7-fluoro-3-(propan-2-yl)-1,4-indazol-1-yl]-1,2,4-oxadiaz-
ol-5-yl}cyclobutyl) [(2-nitrophenyl)sulfonyl]amino}propyl)acetamide
(56 mg) and cesium carbonate (120 mg) in acetonitrile (1 ml) was
added thioglycolic acid (34 .mu.l), and the mixture was stirred at
60.degree. C. for 4 hours. To the reaction solution was added
water, and the mixture was extracted with ethyl acetate (1
ml.times.3). The organic layer was concentrated under reduced
pressure and the residue was purified by silica-gel chromatography
to give the title compound (12 mg).
[0959] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (6H, d, J=7.0 Hz),
1.63-1.75 (2H, m), 1.97 (3H, s), 2.24-2.39 (2H, m), 2.69 (2H, t,
J=6.3 Hz), 2.78-2.90 (2H, m), 3.27-3.59 (6H, m), 6.33-6.46 (1H, m),
7.18-7.28 (2H, m), 7.56-7.63 (1H, m).
[0960] LC-MS, m/z; 415 [M+H]+
[0961] The compounds in the following table (i.e. Examples 567 to
568) were prepared in the same manner as in Example 028 except that
the
3-ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1,1-indazole
trifluoroacetate and
(S)-(-)-1-tert-butoxycarbonyl-2-pyrrolidine-carbaldehyde were
replaced with the corresponding starting compound and
1-acetylpiperidin-4-one, respectively.
##STR00582##
TABLE-US-00080 TABLE 80 Example R.sup.3 R.sup.6 R.sup.7 Compound
Name .sup.1H-NMR/LC-MS, m/z 567.sup.1) Et H F 1-{4-[(3S)-3-
.sup.1H-NMR (CDCl.sub.3) .delta.: {[3-(3-ethyl-7- 1.34-1.54 (5H,
m), 1.59-1.72 (1H, m), fluoro-1H- 1.80-1.94 (2H, m), indazol-1-yl)-
2.03-2.33 (5H, m), 1,2,4-oxadiazol- 2.41-2.52 (1H, m), 2.57-2.97
(5H, m), 5- 3.01-3.16 (5H, m), yl]methyl}pyrrolidin- 3.70-3.81 (1H,
m), 1- 4.32-4.44 (1H, m), 7.19-7.31 (2H, m), yl]piperidin-1-
7.50-7.57 (1H, m). yl}ethanone LC-MS, m/z; 441 [M + H]+ 568.sup.1)
.sup.iPr F H 1-{4-[(3S)-3- .sup.1H-NMR (CDCl.sub.3) .delta.:
({3-[6-fluoro-3- 1.34-1.56 (8H, m), 1.58-1.73 (1H, m),
(propan-2-yl)- 1.80-1.95 (2H, m), 1H-indazol-1- 2.05-2.51 (6H, m),
yl]-1,2,4- 2.60-2.96 (5H, m), 3.04-3.16 (3H, m), oxadiazol-5-
3.41-3.54 (1H, m), yl}methyl)pyrrolidin- 3.77 (1H, d, J = 13.6 Hz),
1- 4.38 (1H, d, J = 13.4 Hz), yl]piperidin-1- 7.07 (1H, td, J =
8.8, 2.3 Hz), yl}ethanone 7.76 (1H, dd, J = 8.8, 5.0 Hz), 7.98 (1H,
dd, J = 9.4, 2.2 Hz). LC-MS, m/z; 455 [M + H]+ .sup.1)Titanium
tetraisopropoxide was added to the reaction system.
Preparations of Examples 569 to 572
[0962] The compounds in the following table (i.e. Examples 569 to
572) were prepared in the same manner as in Example 168 except that
the
3-ethyl-1-(5-{1-[2-(piperidin-4-yl)ethyl]piperidin-4-yl}-1,2,4-oxadiazol--
3-yl)-1H-indazole bis(trifluoroacetate) and methyl chloroformate
were replaced with the corresponding starting compound and
2-methoxyacetyl chloride, respectively.
##STR00583##
[0963] Wherein (R.sup.12-1) means each cyclic amino structure shown
in the following table; and the methoxyacetyl group is attached to
the nitrogen atom in the cyclic amine of (R.sup.12-1). Each free
form of the compounds in the following table was obtained by
omitting the conversion step into hydrochloride in Example 168.
TABLE-US-00081 TABLE 81 Exam- Chemical .sup.1H-NMR/ ple
(R.sup.12-1) Name LC-MS, m/z 569 ##STR00584## 1-{4-[(3R)-3-
({3-[7-fluoro- 3-(propan-2- yl)-1H-indazol- 1-yl]-1,2,4-
oxadiazol-5- yl}methyl) pyrrolidin-1- yl]piperidin- 1-yl}-2-
methoxy- ethanone .sup.1H-NMR (CDCl.sub.3) .delta.: 1.38-1.56 (8H,
m), 1.59-1.73 (1H, m), 1.83-1.95 (2H, m), 2.09-2.34 (2H, m),
2.41-2.52 (1H, m), 2.59-2.95 (5H, m), 3.00-3.14 (3H, m), 3.39-3.55
(4H, m), 3.83 (1H, d, J = 13.2 Hz), 4.01-4.18 (2H, m), 4.36 (1H, d,
J = 11.4 Hz), 7.18-7.28 (2H, m), 7.56-7.62 (1H, m). LC-MS, m/z; 485
[M + H]+ 570 ##STR00585## 1-(3-{[(3R)- 3-({3-[7- fluoro-3-
(propan-2- yl)-1H-indazol- 1-yl]-1,2,4- oxadiazol-5- yl}methyl)
pyrrolidin-1- yl]methyl} azetidin-1- yl)-2- methoxy- ethanone
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (6H, d, J = 7.2 Hz), 1.56-
1.70 (1H, m), 2.07-2.22 (1H, m), 2.36-2.87 (8H, m), 3.06 (2H, d, J
= 6.8 Hz), 3.33-3.56 (4H, m), 3.70 (1H, dd, J = 9.9, 5.1 Hz),
3.85-3.99 (3H, m), 4.08-4.19 (1H, m), 4.25-4.36 (1H, m), 7.19-7.29
(2H, m), 7.56-7.62 (1H, m). LC-MS, m/z; 471 [M + H]+ 571
##STR00586## 1-[(3S)-3- {[(3R)-3- ({3-[7- fluoro-3- (propan-2-
yl)-1H-indazol- 1-yl]-1,2,4- oxadiazol- 5-yl}methyl) pyrrolidin-1-
yl]methyl} pyrrolidin- 1-yl]-2- methoxy- ethanone .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.44-1.79 (8H, m), 1.93-2.37 (10H, m), 3.02-
3.22 (3H, m), 3.35-3.78 (7H, m), 4.03 (2H, s), 7.18-7.29 (2H, m),
7.57-7.63 (1H, m). LC-MS, m/z; 485 [M + H]+ 572 ##STR00587##
1-[(3R)-3- {[(3R)-3- ({3-[7- fluoro-3- (propan-2- yl)-1H-
indazol-1- yl]-1,2,4- oxadiazol-5- yl}methyl) pyrrolidin-1-
yl]methyl} pyrrolidin-1- yl]-2- methoxy- ethanone .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.46-1.79 (8H, m), 2.05-2.21 (2H, m),
2.28-2.83 (8H, m), 3.03-3.20 (3H, m), 3.35-3.78 (7H, m), 3.99-4.04
(2H, m), 7.19-7.29 (2H, m), 7.57-7.62 (1H, m). LC-MS, m/z; 485 [M +
H]+
Preparations of Examples 573 to 576
[0964] The compounds in the following table (i.e. Examples 573 to
576) were prepared in the same manner as in Example 168 except that
the
3-ethyl-1-(5-{1-[2-(piperidin-4-yl)ethyl]piperidin-4-yl}-1,2,4-oxadiazol--
3-yl)-1H-indazole bis(trifluoroacetate) and methyl chloroformate
were replaced with the corresponding starting compound and
2-methoxyacetyl chloride, respectively.
##STR00588##
[0965] Wherein (R.sup.12-1) means each cyclic amino structure shown
in the following table; and the methoxyacetyl group is attached to
the nitrogen atom in the cyclic amine of (R.sup.12-1). Each free
form of the compounds in the following table was obtained by
omitting the conversion step into hydrochloride in Example 168.
TABLE-US-00082 TABLE 82 Exam- Compound .sup.1H-NMR/ ple
(R.sup.12-1) Name LC-MS, m/z 573 ##STR00589## 1-{4-[(3S)- 3-({3-[7-
fluoro-3- (propan-2- yl)-1H- indazol-1- yl]-1,2,4- oxadiazol-5-
yl}methyl) pyrrolidin-1- yl]piperidin- 1-yl}-2- methoxy- ethanone
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.38-1.56 (8H, m), 1.59-1.73 (1H,
m), 1.83-1.95 (2H, m), 2.09-2.34 (2H, m), 2.41-2.52 (1H, m),
2.59-2.95 (5H, m), 3.00-3.14 (3H, m), 3.39-3.55 (4H, m), 3.83 (1H,
d, J = 13.2 Hz), 4.01- 4.18 (2H, m), 4.36 (1H, d, J = 11.4 Hz),
7.18-7.28 (2H, m), 7.56-7.62 (1H, m). LC-MS, m/z; 485 [M + H]+ 574
##STR00590## 1-(3-{[(3S)- 3-({3-[7- fluoro-3- (propan-2- yl)-1H-
indazol-1- yl]-1,2,4- oxadiazol-5- yl}methyl) pyrrolidin-1-
yl]methyl} azetidin-1- yl)-2- methoxy- ethanone 1H-NMR (CDCl.sub.3)
.delta.: 1.50 (6H, d, J = 7.2 Hz), 1.56-1.70 (1H, m), 2.07-2.22
(1H, m), 2.36-2.87 (8H, m), 3.06 (2H, d, J = 6.8 Hz), 3.33-3.56
(4H, m), 3.70 (1H, dd, J = 9.9, 5.1 Hz), 3.85- 3.99 (3H, m), 4.08-
4.19 (1H, m), 4.25- 4.36 (1H, m), 7.19- 7.29 (2H, m), 7.56- 7.62
(1H, m). LC-MS, m/z; 471 [M + H]+ 575 ##STR00591## 1-[(3S)-3-
{[(3S)-3- ({3-[7- fluoro-3- (propan-2- yl)-1H- indazol-1-
yl]-1,2,4- oxadiazol-5- yl}methyl) pyrrolidin-1- yl]methyl}
pyrrolidin-1- yl]-2- methoxy- ethanone .sup.1H-NMR (CDCl.sub.3)
.delta.: 1.46-1.79 (8H, m), 2.05-2.21 (2H, m), 2.28-2.83 (8H, m),
3.03-3.20 (3H, m), 3.35-3.78 (7H, m), 3.99-4.04 (2H, m), 7.19-7.29
(2H, m), 7.57-7.62 (1H, m). LC-MS, m/z; 485 [M + H]+ 576
##STR00592## 1-[(3R)-3- {[(3S)-3- ({3-[7- fluoro-3- (propan-2-
yl)-1H- indazol-1- yl]-1,2,4- oxadiazol-5- yl}methyl) pyrrolidin-1-
yl]methyl} pyrrolidin-1- yl]-2- methoxy- ethanone .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.44-1.79 (8H, m), 1.93-2.87 (10H, m),
3.02-3.22 (3H, m), 3.35-3.78 (7H, m), 4.03 (2H, s), 7.18-7.29 (2H,
m), 7.57-7.63 (1H, m). LC-MS, m/z; 485 [M + H]+
[0966] The compounds in the following table (i.e. Examples 577 to
579) were prepared in the same manner as in Example 001 except that
the tert-butyl
4-[3-(3-ethyl-6-fluoro-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]piperidin-1--
carboxylate was replaced with the corresponding starting compound
(see, Reference Examples 147 to 149).
##STR00593##
TABLE-US-00083 TABLE 83 Exam- Compound .sup.1H-NMR/ ple (B-2) Name
LC-MS, m/z 577 ##STR00594## 7-fluoro-1- [5-(3-methyl- piperidin-4-
yl)-1,2,4- oxadiazol-3- yl]-3-(propan- 2-yl)-1H- indazole
trifluoro- acetate LC-MS, m/z; 344 [M + H]+ 578 ##STR00595##
7-fluoro-1- {5-[(3S,4S)-3- methoxy- piperidin-4- yl]-1,2,4-
oxadiazol-3- yl}-3-(propan- 2-yl)-1H- indazole trifluoro- acetate
and 7-fluoro-1- {5-[(3R,4R)- 3-methoxy- piperidin-4- yl]-1,2,4-
oxadiazol-3- yl}-3-(propan- 2-yl)-1H- indazole trifluoro- acetate
LC-MS, m/z; 360 [M + H]+ .sup.1H-NMR (CDCl.sub.3) .delta.: 1.48
(6H, d, J = 7.0 Hz), 2.31- 2.75 (2H, m), 3.12-3.56 (7H, m),
3.61-3.84 (2H, m), 4.24 (1H, s), 7.18- 7.29 (2H, m), 7.58 (1H, d, J
= 7.7 Hz), 9.46-9.95 (1H, m). 579 ##STR00596## 7-fluoro-1-
[5-(4-methyl- piperidin-4- yl)-1,2,4- oxadiazol-3- yl]-3-(propan-
2-yl)-1H- indazole trifluoro- acetate LC-MS, m/z; 344 [M + H]+
[0967] The compounds in the following table (i.e. Examples 580 to
581) were prepared in the same manner as in Example 028 except that
the 3-ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and
(S)-(-)-1-tert-butoxycarbonyl-2-pyrrolidine-carbaldehyde were
replaced with the corresponding starting compound and
1-acetylpiperidin-4-one, respectively.
##STR00597##
Wherein (B-2) means each cyclic amino structure shown in the
following table, and the N-acetylpiperidyl group is attached to the
nitrogen atom in the cyclic amine of (B-2).
TABLE-US-00084 TABLE 84 Exam- Compound .sup.1H-NMR/ ple (B-2) Name
LC-MS, m/z 580.sup.1) ##STR00598## 1-(4-{3- [7-fluoro-3- (propan-2-
yl)-1H- indazol-1- yl]-1,2,4- oxadiazol-5- yl}-3- methyl-1,4'-
bipiperidin- 1'-yl) ethanone LC-MS, m/z; 469 [M + H]+ 581.sup.1)
##STR00599## 1-(4-{3-[7- fluoro-3- (propan-2- yl)-1H- indazol-1-
yl]-1,2,4- oxadiazol-5- yl}-4- methyl-1,4'- bipiperidin- 1'-yl)
ethanone .sup.1H-NMR (CDCl.sub.3) .delta.: 1.34-1.57 (11H, m),
1.75-1.91 (4H, m), 2.08 (3H, s), 2.35-2.59 (6H, m), 2.74-2.87 (2H,
m), 2.95-3.09 (1H, m), 3.42-3.55 (1H, m), 3.84 (1H, d, J = 11.2
Hz), 4.63 (1H, d, J = 13.2 Hz), 7.16-7.28 (2H, m), 7.56-7.63 (1H,
m). LC-MS, m/z; 469 [M + H]+ .sup.1)Titanium tetraisopropoxide was
added to the reaction system.
Preparations of Examples 582 to 584
##STR00600##
[0968] Wherein HX means hydrochloric acid or trifluoroacetic acid;
(R.sup.12-1) means each cyclic amino structure shown in the
following table; and the hydroxyacetyl group is attached to the
nitrogen atom in the cyclic amine of (R.sup.12-1).
[0969] The compounds in the following table (i.e. Examples 582 to
584) were prepared in the same manner as in Example 242 or the 2 N
sodium hydroxide aqueous solution was replaced with methyl
amine/methanol, provided that the
4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-1,4-
'-bipiperidine dihydrochloride was replaced with the corresponding
starting compound. Each hydrochloride in the following table was
obtained by treating a solution of the prepared compound in
dichloromethane with 1N HCl/diethyl ether.
TABLE-US-00085 TABLE 85 Exam- Compound .sup.1H-NMR/ ple R.sup.3
(R.sup.12-1) Name LC-MS, m/z 582 Et ##STR00601## 1-[(3S)-3- ({4-[3-
(3-ethyl- 7-fluoro- 1H-indazol- 1-yl)-1,2,4- oxadiazol-5-
yl]piperidin- 1-yl}methyl) pyrrolidin-1- yl]-2- hydroxy- ethanone
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (3H, t, J = 7.6 Hz),
1.50-1.85 (2H, m), 1.96-2.62 (10H, m), 2.83-3.13 (3H, m), 3.03 (2H,
q, J = 7.6 Hz), 3.18-3.57 (3H, m), 3.63-3.30 (1H, m), 4.02-4.13
(2H, m), 7.20-7.31 (2H, m), 7.50-7.57 (1H, m). LC-MS, m/z; 457 [M +
H]+ 583 Et ##STR00602## 1-[(2S)-2- ({4-[3-(3- ethyl-7- f luoro-1H-
indazol-1- yl)-1,2,4- oxadiazol-5- yl]piperidin- 1-yl}methyl)
pyrrolidin-1- yl]-2- hydroxy- ethanone .sup.1H-NMR (CDCl.sub.3)
.delta.: 1.44 (3H, t, J = 7.5 Hz), 1.80- 2.40 (11.3H, m, rotamer),
2.61-2.69 (0.7H, m, rotamer), 2.80-3.29 (6H, m), 3.29-3.38 (0.7H,
m, rotamer), 3.45-3.55 (1H, m), 3.60-3.70 (0.3H, m, rotamer),
3.81-3.90 (0.3H, m, rotamer), 4.00-4.11 (1.4H, m, rotamer), 4
.12-4.38 (1.3H, m, rotamer), 7.18-7.30 (2H, m), 7.48-7.56 (1H, m).
LC-MS, m/z; 457 [M + H]+ 584 .sup.iPr ##STR00603## 1-[(3S,4S)-4-
{3-[7-fluoro- 3-(propan-2- yl)-1H- indazol-1- yl]-1,2,4-
oxadiazol-5- yl}-3- methoxy-1,4'- bipiperidin- 1'-yl]-2- hydroxy-
ethanone hydro- chloride and 1-((3R, 4R)-4-{3- [7-fluoro-3-
(propan-2- yl)-1H- indazol-1- yl]-1,2,4- oxadiazol-5- yl}-3-
methoxy-1,4'- bipiperidin- 1'-yl]-2- hydroxy- ethanone hydro-
chloride .sup.1H-NMR (CD.sub.3OD) .delta.: 1.08-1.23 (2H, m), 1.47
(6H, d, J = 5.9 Hz), 1.60-1.94 (2H, m), 2.07-2.35 (2H, m),
2.38-2.72 (2H, m), 2.72-2.87 (1H, m), 3.08-3.53 (7H, m), 3.56-3.76
(3H, m), 3.84-4.07 (2H, m), 4.14-4.50 (2H, m), 4.63-4.77 (1H, m),
7.26-7.40 (2H, m), 7.67-7.80 (1H, m). LC-MS, m/z; 501 [M + H]+
Preparation of Examples 585-589
[0970] The compounds in the following table (i.e. Examples 585 to
589) were prepared in the same manner as in Example 168 except that
the
3-ethyl-1-(5-{1-[2-(piperidin-4-yl)ethyl]piperidin-4-yl}-1,2,4-oxadiazol--
3-yl)-1H-indazole bis(trifluoroacetate) and methyl chloroformate
were replaced with the corresponding starting compound, and acid
chloride (R--Cl) or acetic anhydride, respectively.
##STR00604##
Wherein HX means hydrochloric acid or trifluoroacetic acid;
(R.sup.12-1) means each cyclic amino structure shown in the
following table; R means each structure shown in the following
table; and R is attached to the nitrogen atom in the cyclic amine
of (R.sup.12-1). Each free form of the compounds in the following
table was obtained by omitting the conversion step into
hydrochloride in Example 168.
TABLE-US-00086 TABLE 86 Example (R.sup.12-1) R Compound Name
.sup.1H-NMR/LC-MS, m/z 585 ##STR00605## --Ms 7-fluoro-1-
[5-(1-{[(3S)- 1-(methyl- sulfonyl) pyrrolidin-3- yl]methyl}
piperidin-4- yl)-1,2,4- oxadiazol-3- yl]-3- (propan-2- yl)-1H-
indazole .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (6H, d, J = 6.8
Hz), 1.63-1.77 (1H, m), 1.96- 2.26 (7H, m), 2.29-2.43 (2H, m),
2.43-2.58 (1H, m), 2.84 (3H, s), 2.86- 3.13 (4H, m), 3.28-3.38 (1H,
m), 3.39-3.53 (3H, m), 7.18-7.28 (2H, m), 7.55-7.63 (1H, m). LC-MS,
m/z; 491 [M + H]+ 586 ##STR00606## --Ms 7-fluoro-1- [5-(1-{[(3R)-
1-(methyl- sulfonyl) pyrrolidin-3- yl]methyl} piperidin-4-
yl)-1,2,4- oxadiazol-3- yl]-3- (propan-2- yl)-1H- indazole
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (6H, d, J = 6.8 Hz),
1.63-1.77 (1H, m), 1.96- 2.26 (7H, m), 2.29-2.43 (2H, m), 2.43-2.58
(1H, m), 2.84 (3H, s), 2.86- 3.13 (4H, m), 3.28-3.38 (1H, m),
3.39-3.53 (3H, m), 7.18-7.28 (2H, m), 7.55-7.63 (1H, m). LC-MS,
m/z; 491 [M + H]+ 587 ##STR00607## --Ac 1-(4-{3-[7- fluoro-3-
(propan-2- yl)-1H- indazol-1- yl]-1,2,4- oxadiazol-5- yl}-3'-
methyl-1,4'- bipiperidin- 1'-yl)ethanone .sup.1H-NMR (CDCl.sub.3)
.delta.: 0.88- 0.97 (3H, m), 1.50 (6H, d, J = 7.2 Hz), 1.73-1.89
(2H, m), 1.98-2.30 (11H, m), 2.40-2.65 (1H, m), 2.96-3.21 (4H, m),
3.41- 3.56 (1H, m), 3.62-3.92 (1H, m), 4.51-4.78 (1H, m), 7.18-7.30
(2H, m), 7.56-7.64 (1H, m). LC-MS, m/z; 469 [M + H]+ 588
##STR00608## ##STR00609## 1-(4-{3-[7- fluoro-3- (propan-2- yl)-1H-
indazol-1- yl]-1,2,4- oxadiazol-5- yl}-3'- methyl-1,4'-
bipiperidin- 1'-yl)-2- methoxy- ethanone .sup.1H-NMR (CDCl.sub.3)
.delta.: 0.84- 0.99 (3H, m), 1.50 (6H, d, J = 7.0 Hz), 1.75-1.88
(2H, m), 1.93-2.30 (7H, m), 2.42-2.74 (1H, m), 2.87-3.22 (4H, m),
3.38- 3.57 (5H, m), 3.67-4.01 (1H, m), 4.04-4.28 (2H, m), 4.45-4.77
(1H, m), 7.18-7.32 (2H, m), 7.55- 7.63 (1H, m). LC-MS, m/z; 499 [M
+ H]+ 589 --Ms 4-{3-[7- fluoro-3- (propan-2- yl)-1H- indazol-1-
yl]-1,2,4- oxadiazol-5- yl}-3'- methyl-1'- (methyl- sulfonyl)-1,4'-
bipiperidine .sup.1H-NMR (CDCl.sub.3) .delta.: 1.04 (3H, d, J = 6.8
Hz), 1.40-1.76 (8H, m), 1.79- 1.91 (1H, m), 1.96-2.30 (8H, m),
2.50-2.88 (5H, m), 2.97-3.17 (2H, m), 3.39-3.54 (1H, m), 3.56- 3.71
(1H, m), 3.80-3.90 (1H, m), 7.15-7.26 (2H, m), 7.54-7.61 (1H, m).
LC-MS, m/z; 505 [M + H]+
Preparations of Examples 590-610
##STR00610##
[0971] Wherein X means each structure shown in the following
table.
[0972] The compounds in the following table (i.e. Examples 590 to
610) were prepared in the same manner as in Example 272 except that
the
4-[3-(3-ethyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]cyclohexanone
and morpholine were replaced with
3-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}cycl-
obutanone and the corresponding amine, respectively.
TABLE-US-00087 TABLE 87 Example X Compound Name .sup.1H-NMR/LC-MS,
m/z 590 ##STR00611## 1-(4-{[(cis-3-{3- [7-fluoro-3-
(propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5- yl}cyclobutyl)
amino]methyl] piperidin-1-yl) ethanone .sup.1H-NMR (CDCl.sub.3)
.delta.: 0.99-1.23 (2H, m), 1.47 (6H, d, J = 7.0 Hz), 1.56-1.89
(3H, m), 2.06 (3H, s), 2.20-2.33 (2H, m), 2.40-2.59 (3H, m),
2.69-2.88 (2H, m), 2.94-3.10 (1H, m), 3.28-3.55 (3H, m), 3.79 (1H,
d, J = 13.9 Hz), 4.60 (1H, d, J = 13.9 Hz), 7.14-7.26 (2H, m),
7.52-7.60 (1H, m). LC-MS, m/z; 455 [M + H]+ 591 ##STR00612##
1-{(3S)-3-[(3-{3- [7-fluoro-3- (propan-2-yl)-1H- indazol-1-yl]-
1,2,4-oxadiazol-5- yl}cyclobutyl) amino]pyrrolidin- 1-yl}ethanone
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.47 (6H, dd, J = 7.1, 0.8 Hz),
1.65-2.21 (6H, m), 2.27-2.50 (2H, m), 2.78-2.93 (2H, m), 3.16-3.71
(7H, m), 7.16-7.26 (2H, m), 7.53-7.59 (1H, m). LC-MS, m/z; 427 [M +
H]+ 592 ##STR00613## 1-{(3R)-3-[(3-{3- [7-fluoro-3-
(propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5- yl}cyclobutyl)
amino]pyrrolidin- 1-yl}ethanone .sup.1H-NMR (CDCl.sub.3) .delta.:
1.47 (6H, dd, J = 7.1, 0.8 Hz), 1.65-2.21 (6H, m), 2.27-2.50 (2H,
m), 2.78-2.93 (2H, m), 3.16-3.71 (7H, m), 7.16-7.26 (2H, m),
7.53-7.59 (1H, m). LC-MS, m/z; 427 [M + H]+ 593 ##STR00614##
1-{4-[(cis-3-{3- [7-fluoro-3- (propan-2-yl)-1H- indazol-1-yl]-
1,2,4-oxadiazol-5- yl}cyclobutyl) amino]piperidin-1- yl}ethanone
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.18-1.36 (2H, m), 1.46 (6H, d, J
= 7.0 Hz), 1.77-1.92 (2H, m), 2.04-2.07 (3H, m), 2.22-2.37 (2H, m),
2.63-2.91 (4H, m), 3.00-3.15 (1H, m), 3.37-3.55 (3H, m), 3.77 (1H,
d, J = 13.8 Hz), 4.43 (1H, d, J = 13.4 Hz), 7.14-7.26 (2H, m),
7.54-7.59 (1H, m). LC-MS, m/z; 441 [M + H]+ 594 ##STR00615##
cis-3-{3-[7- fluoro-3-(propan- 2-yl)-1H-indazol- 1-yl]-1,2,4-
oxadiazol-5-yl}-N- {[1- (methylsulfonyl) piperidin-4- yl]methyl}
cyclobutanamine .sup.1H-NMR (CDCl.sub.3) .delta.: 1.16- 1.21 (1H,
m), 1.30 (2H, ddd, J = 25.1, 12.6, 4.6 Hz), 1.43-1.59 (7H, m),
1.66-1.93 (3H, m), 2.20-2.35 (1H, m), 2.50 (2H, d, J = 6.6 Hz),
2.62 (2H, td, J = 11.9, 2.4 Hz), 2.71-2.88 (4H, m), 3.27-3.54 (3H,
m), 3.80 (2H, d, J = 11.7 Hz), 7.15-7.26 (2H, m), 7.54-7.60 (1H,
m). LC-MS, m/z; 491 [M + H]+ 595 ##STR00616## N-(3-{3-[7-fluoro-
3-(propan-2-yl)- 1H-indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}cyclobutyl) tetrahydro-2H- pyran-4-amine LC-MS, m/z; 400 [M +
H]+ 596 ##STR00617## cis-3-{3-[7- fluoro-3-(propan-
2-yl)-1H-indazol- 1-yl]-1,2,4- oxadiazol-5-yl}-N- (tetrahydrofuran-
2-ylmethyl) cyclobutanamine LC-MS, m/z; 400 [M + H]+ 597
##STR00618## cis-3-{3-[7- fluoro-3-(propan- 2-yl)-1H-indazol-
1-yl]-1,2,4- oxadiazol-5-yl}-N- [2-(tetrahydro-2H- pyran-2-
yl)ethyl] cyclobutanamine LC-MS, m/z; 428 [M + H]+ 598 ##STR00619##
trans-3-{3-[7- fluoro-3-(propan- 2-yl)-1H-indazol- 1-yl]-1,2,4-
oxadiazol-5-yl}-N- [2-(tetrahydro-2H- pyran-2- yl)ethyl]
cyclobutanamine LC-MS, m/z; 428 [M + H]+ 599 ##STR00620##
3-{3-[7-fluoro-3- (propan-2-yl)-1H- indazol-1-yl]-
1,2,4-oxadiazol-5- yl}-N-[2- (tetrahydrofuran- 3-yl)ethyl]
cyclobutanamine LC-MS, m/z; 414 [M + H]+ 600 ##STR00621##
N-(3-{3-[7-fluoro- 3-(propan-2-yl)- 1H-indazol-1-yl]-
l,2,4-oxadiazol-5- yl}cyclobutyl) tetrahydro-2H- pyran-3-amine
LC-MS, m/z; 400 [M + H]+ 601 ##STR00622## 3-{3-[7-fluoro-3-
(propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}-N-{tetrahydro- 2H-pyran-3- ylmethyl) cyclobutanamine LC-MS,
m/z; 414 [M + H]+ 602 ##STR00623## 3-{3-[7-fluoro-3-
(propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}-N-(tetrahydro- 2H-pyran-2- ylmethyl) cyclobutanamine LC-MS,
m/z; 414 [M + H]+ 603 ##STR00624## 3-{3-[7-fluoro-3-
(propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5- yl}-N-[2-
(tetrahydro-2H- pyran-4- yl)ethyl] cyclobutanamine LC-MS, m/z; 450
[M + Na]+ 604 ##STR00625## 3-{3-[7-fluoro-3- (propan-2-yl)-1H-
indazol-1-yl]- 1,2,4-oxadiazol-5- yl}-N-[2- (tetrahydro-2H-
pyran-3- yl)ethyl] cyclobutanamine LC-MS, m/z; 450 [M + Na]+ 605
##STR00626## 3-{3-[7-fluoro-3- (propan-2-yl)-1H- indazol-1-yl]-
1,2,4-oxadiazol-5- yl}-N-(2- methoxyethyl) cyclobutanamine LC-MS,
m/z; 374 [M + H]+ 606 ##STR00627## N-(3-{3-[7-fluoro-
3-(propan-2-yl)- 1H-indazol-1-yl]- 1,2,4-oxadiazol-5-
yl}cyclobutyl) oxetan-3-amine LC-MS, m/z; 394 [M + Na]+ 607
##STR00628## N-(3-{3-[7-fluoro- 3-(propan-2-yl)- 1H-indazol-1-yl] -
1,2,4-oxadiazol-5- yl)cyclobutyl) tetrahydrofuran-3- amine LC-MS,
m/z; 386 [M + H]+ 608 ##STR00629## 3-{3-[7-fluoro-3-
(propan-2-yl)-1H- indazol-1-yl]- 1,2,4-oxadiazol-5- yl}-N-
(tetrahydrofuran- 3-ylmethyl) cyclobutanamine LC-MS, m/z; 400 [M +
H]+ 609 ##STR00630## 3-{3-[7-fluoro-3- (propan-2-yl)-1H-
indazol-1-yl]- 1,2,4-oxadiazol-5- yl}-N-(3- methoxypropyl)
cyclobutanamine LC-MS, m/z; 388 [M + H]+ 610 ##STR00631##
3-{3-[7-fluoro-3- (propan-2-yl)-1H- indazol-1-yl]-
1,2,4-oxadiazol-5- yl}-N-(tetrahydro- 2H-pyran-4- ylmethyl)
cyclobutanamine LC-MS, m/z; 414 [M + H]+
Preparations of Examples 611 to 615
[0973] The compounds in the following table (i.e. Examples 611 to
615) were prepared in the same manner as in Example 097 except that
the
3-ethyl-6-fluoro-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and ethyl iodide were replaced with the
corresponding starting compound (see, Examples 595, 596, and 610)
and R.sub.2--X, respectively.
##STR00632##
Wherein R.sub.2--X means N-(2-chloroethyl)acetamide or
1-bromo-2-methoxyethane. Each free form of the compounds in the
following table was obtained by omitting the conversion step into
hydrochloride in Example 097.
TABLE-US-00088 TABLE 88 Example R.sup.1 R.sup.2 Compound Name
.sup.1H NMR/LC-MS, m/z 611 ##STR00633## ##STR00634##
N-{2-[(3-{3-[7- fluoro-3-(propan-2- yl)-1H-indazol-1-
yl]-1,2,4-oxadiazol- 5-yl}cyclobutyl) (tetrahydro-2H-
pyran-4-yl)amino] ethyl}acetamide LC-MS, m/z; 507 [M + Na]+ 612
##STR00635## ##STR00636## 3-{3-[7-fluoro-3- (propan-2-yl)-1H-
indazol-1-yl]-1,2,4- oxadiazol-5-yl}-N- (2-methoxyethyl)-N-
(tetrahydrofuran-2- ylmethyl) cyclobutanamine LC-MS, m/z; 458 [M +
H]+ 613 ##STR00637## 3-{3-[7-fluoro-3- (propan-2-yl)-1H-
indazol-1-yl]-1,2,4- oxadiazol-5-yl}-N- (2-methoxyethyl)-N-
{tetrahydro-2H- pyran-4- ylmethyl) cyclobutanamine LC-MS, m/z; 494
[M + Na]+ 614 ##STR00638## N-(cis-3-{3-[7- fluoro-3-(propan-2-
yl)-1H-indazol-1- yl]-1,2,4-oxadiazol- 5-yl}cyclobutyl)-N-
(2-methoxyethyl) tetrahydro-2H- pyran-4-amine LC-MS, m/z; 458 [M +
H]+ 615 ##STR00639## ##STR00640## N-(trans-3-{3-[7-
fluoro-3-(propan-2- yl)-1H-indazol-1- yl]-1,2,4-oxadiazol-
5-yl}cyclobutyl)-N- (2-methoxyethyl) tetrahydro-2H- pyran-4-amine
LC-MS, m/z; 458 [M + H]+
Preparations of Examples 616 to 623
##STR00641##
[0974] Wherein X means each structure shown in the following
table.
[0975] The compounds in the following table (i.e. Examples 616 to
623) were prepared in the same manner as in Example 272 except that
the
4-[3-(3-ethyl-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]cyclohexanone
and morpholine were replaced with
4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}cycl-
ohexanone and the corresponding amine, respectively.
TABLE-US-00089 TABLE 89 Example X Compound Name .sup.1H NMR/LC-MS,
m/z 616 ##STR00642## N-(cis-4-{3-[7-fluoro-3-
(propan-2-yl)-1H-indazol- 1-yl]-1,2,4-oxadiazol-5-
yl}cyclohexyl)-1- (methylsulfonyl) pyrrolidin-3-amine LC-MS, m/z;
491 [M + H]+ 617 ##STR00643## cis-4-{3-[7-fluoro-3-
(propan-2-yl)-1H-indazol- 1-yl]-1,2,4-oxadiazol-5- yl}-N-{2- [1-
(methylsulfonyl) azetidin-3-yl]ethyl} cyclohexanamine LC-MS, m/z;
527 [M + Na]+ 618 ##STR00644## cis-4-{3-[7-fluoro-3-
(propan-2-yl)-1H-indazol- 1-yl]-1,2,4-oxadiazol-5- yl}-N-{[1-
(methylsulfonyl) piperidin-4-yl]methyl} cyclohexanamine LC-MS, m/z;
519 [M + H]+ 619 ##STR00645## 4-{3-[7-fluoro-3-(propan-
2-yl)-1H-indazol-1-yl]- 1,2,4-oxadiazol-5-yl}-N-
[2-(tetrahydro-2H-pyran- 3-yl)ethyl] cyclohexanamine LC-MS, m/z;
456 [M + H]+ 620 ##STR00646## trans-4-{3-[7-fluoro-3-
(propan-2-yl)-1H-indazol- 1-yl]-1,2,4-oxadiazol-5-
yl}-N-(tetrahydrofuran-2- ylmethyl)cyclohexanamine LC-MS, m/z; 428
[M + H]+ 621 ##STR00647## 4-{3-[7-fluoro-3-(propan-
2-yl)-1H-indazol-1-yl]- 1,2,4-oxadiazol-5-yl}-N- (2-methoxyethyl)
cyclohexanamine LC-MS, m/z; 402 [M + H]+ 622 ##STR00648##
1-{3-[(cis-4-{3-[7- fluoro-3-(propan-2-yl)- 1H-indazol-1-yl]-1,2,4-
oxadiazol-5- yl}cyclohexyl)amino] piperidin-1-yl}ethanone LC-MS,
m/z; 469 [M + H]+ 623 ##STR00649## N-(cis-4-{3-[7-fluoro-3-
(propan-2-yl)-1H-indazol- 1-yl]-1,2,4-oxadiazol-5- yl}cyclohexyl)
tetrahydro-2H- pyran-3-amine LC-MS, m/z; 428 [M + H]+
Example 624
Preparation of
1-{4-[3-(7-fluoro-3-methoxy-1H-indazol-1-yl)-1,2,4-oxadiazol-5-yl]-1,4'-b-
ipiperidin-1'-yl}ethanone
##STR00650##
[0977] The title compound was prepared in the same manner as in
Example 334 except that the
7-fluoro-N'-hydroxy-3-(propan-2-yl)-1H-indazole-1-carboximidamide
and 1'-(tert-butoxycarbonyl)-1,4'-bipiperidine-4-carboxylic acid
were replaced with
7-fluoro-N'-hydroxy-3-methoxy-1H-indazole-1-carboximidamide and
1'-acetyl-1,4'-bipiperidine-4-carboxylic acid, respectively, and
the tetramethyl ammonium hydroxide aqueous solution was replaced
with 1M tetrabutylammonium fluoride/THF.
[0978] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.36-1.57 (2H, m),
1.78-2.25 (9H, m), 2.30-2.45 (2H, m), 2.48-2.63 (2H, m), 2.92-3.11
(4H, m), 3.87 (1H, d, J=13.4 Hz), 4.20 (3H, s), 4.66 (1H, d, J=13.2
Hz), 7.16-7.29 (2H, m), 7.46-7.54 (1H, m).
[0979] LC-MS, m/z; 443 [M+H]+
Preparations of Examples 625 to 626
[0980] The compounds in the following table (i.e. Examples 625 to
626) were prepared in the same manner as in Example Example 028
except that the
3-ethyl-1-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indazole
trifluoroacetate and
(S)-(-)-1-tert-butoxycarbonyl-2-pyrrolidine-carbaldehyde were
replaced with the corresponding starting compound and the
corresponding ketone compound, respectively.
##STR00651##
Wherein (R.sup.12-1) means each cyclic amino structure shown in the
following table; HX means hydrochloric acid or trifluoroacetic
acid; and Boc group is attached to the nitrogen atom in the cyclic
amine of (R.sup.12-1).
TABLE-US-00090 TABLE 90 Exam- Compound .sup.1H-NMR/ ple R.sup.3
(R.sup.12-1) Name LC-MS, m/z 625 .sup.iPr ##STR00652## tert-butyl
3-(4- {3-[7-fluoro-3- (propan-2-yl)- 1H-indazol-1- yl]-1,2,4-
oxadiazol-5- yl}piperidin-1- yl)azetidine-1- carboxylate LC-MS,
m/z; 485 [M + H]+ 626.sup.1) Et ##STR00653## tert-butyl 4-[3-
(3-ethyl-7- fluoro-1H- indazol-1-yl)- 1,2,4-oxadiazol- 5-yl]-3'-
methyl-1,4'- bipiperidine-1'- carboxylate LC-MS, m/z; 513 [M + H]+
.sup.1)Titanium tetraisopropoxide was added to the reaction
system.
Preparations of Examples 627 to 628
[0981] The compounds in the following table (i.e. Examples 627 to
628) were prepared in the same manner as in Example 054 except that
the tert-butyl
3-[(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-
piperidin-1-yl)methyl]azetidine-1-carboxylate was replaced with the
corresponding starting compound.
##STR00654##
Wherein HX means trifluoroacetic acid.
TABLE-US-00091 TABLE 91 Exam- Compound ple R.sup.3 (R.sup.12-1)
Name LC-MS, m/z 627 .sup.iPr ##STR00655## 1-{5-[1- (azetidin-3-
yl)piperidin- 4-yl]-1,2,4- oxadiazol-3- yl}-7-fluoro- 3-(propan-2-
yl)-1H- indazole bis (trifluoro- acetate) LC-MS, m/z; 385 [M + H]+
628 Et ##STR00656## 4-[3-(3-ethyl- 7-fluoro-1H- indazol-1-yl)-
1,2,4-oxadiazol- 5-yl]-3'- methyl-1,4'- bipiperidine bis
(trifluoro- acetate) LC-MS, m/z; 413 [M + H]+
Preparations of Examples 629 to 633
[0982] The compounds in the following table (i.e. Examples 629 to
633) were prepared in the same manner as in Example 168 except that
the
3-ethyl-1-(5-{1-[2-(piperidin-4-yl)ethyl]piperidin-4-yl}-1,2,4-oxadiazol--
3-yl)-1H-indazole bis(trifluoroacetate) and methyl chloroformate
were replaced with the corresponding starting compound and an acid
chloride (R--Cl) or acetic anhydride, respectively.
##STR00657##
Wherein HX means hydrochloric acid or trifluoroacetic acid;
(R.sup.12-1) means each cyclic amino structure shown in the
following table; R means each structure shown in the following
table; and R is attached to the nitrogen atom in the cyclic amine
of (R.sup.12-1). Each free form of the compounds in the following
table was obtained by omitting the conversion step into
hydrochloride in Example 168.
TABLE-US-00092 TABLE 92 Example R.sup.3 R.sup.6 (R.sup.12-1) R
Compound Name .sup.1H NMR/LC-MS, m/z 629 .sup.iPr F ##STR00658## Ms
4-{3-[6,7- difluoro-3- (propan-2-yl)- 1H-indazol-1- yl]-1,2,4-
oxadiazol-5- yl}-1'- (methylsulfonyl)- 1,4'-bipiperidine
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.48 (6H, d, J = 7.1 Hz),
1.61-1.77 (2H, m), 1.84-1.95 (2H, m), 1.95-2.10 (2H, m), 2.12-2.25
(2H, m), 2.34-2.50 (3H, m), 2.66-2.77 (2H, m), 2.79 (3H, s),
2.91-3.10 (3H, m), 3.37-3.52 (1H, m), 3.78-3.90 (2H, m), 7.10-7.20
(1H, m), 7.46-7.53 (1H, m). LC-MS, m/z; 509 [M + H]+ 630 Et F
4-[3-(3-ethyl- 6,7-difluoro- 1H-indazol-1- yl)-1,2,4- oxadiazol-5-
yl]-1'- (methylsulfonyl)- 1,4'-bipiperidine .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.43 (3H, t, J = 7.6 Hz), 1.61-1.76 (2H, m),
1.85-1.95 (2H, m), 1.97-2.10 (2H, m), 2.14-2.24 (2H, m), 2.35-2.50
(3H, m), 2.66-2.77 (2H, m), 2.79 (3H, s), 2.93-3.10 (5H, m),
3.80-3.90 (2H, m), 7.13-7.22 (1H, m), 7.42-7.48 (1H, m). LC-MS,
m/z; 495 [M + H]+ 631 Et H ##STR00659## Ac 1-{4-[3-(3- ethyl-7-
fluoro-1H- indazol-1-yl)- 1,2,4- oxadiazol-5- yl]-3'-methyl-
1,4'-bipiperidin- 1'-yl}ethanone .sup.1H-NMR (CDCl.sub.3) .delta.:
0.83-0.98 (3H, m), 1.23-1.51 (4H, m), 1.71-2.29 (12H, m), 2.38-2.63
(1H, m), 2.88-3.22 (6H, m), 3.60-3.89 (1H, m), 4.49-4.78 (1H, m),
7.16-7.32 (2H, m), 7.45-7.59 (1H, m). LC-MS, m/z; 455 [M + H]+ 632
##STR00660## 1-{4-[3-(3- ethyl-7- fluoro-1H- indazol-1-yl)- 1,2,4-
oxadiazol-5- yl]-3'-methyl- 1,4'-bipiperidin- 1'-yl}-2- methoxy-
ethanone .sup.1H-NMR (CDCl.sub.3) .delta.: 0.87-0.98 (3H, m),
1.20-1.62 (4H, m), 1.76-1.87 (2H, m), 1.95-2.29 (8H, m), 2.43-2.71
(1H, m), 2.86-3.16 (6H, m), 3.42 (3H, d, J = 2.9 Hz), 3.66-3.99
(1H, m), 4.03-4.24 (2H, m), 4.47-4.73 (1H, m), 7.20-7.30 (2H, m),
7.48-7.58 (1H, m) LC-MS, m/z; 485 [M + H]+ 633 Ms 4-[3-(3-ethyl-
7-fluoro-1H- indazol-1-yl)- 1,2,4- oxadiazol-5- yl]-3'-methyl - 1'-
(methyl- sulfonyl)-1,4'- bipiperidine .sup.1H-NMR (CDCl.sub.3)
.delta.: 1.04 (3H, d, J = 6.8 Hz), 1.42 (3H, t, J = 7.6 Hz),
1.60-1.88 (2H, m), 1.94-2.27 (9H, m), 2.53-2.67 (1H, m), 2.75 (3H,
s), 2.97-3.13 (5H, m), 3.56-3.66 (1H, m), 3.78-3.87 (1H, m),
7.16-7.29 (2H, m), 7.47-7.54 (1H, m). LC-MS, m/z; 491 [M + H]+
Preparations of Examples 634 to 636
##STR00661##
[0984] Wherein HX means hydrochloric acid or trifluoroacetic acid;
and (R.sup.12-1) means each cyclic amino structure shown in the
following table; and the hydroxyacetyl group is attached to the
nitrogen atom in the cyclic amine of (R.sup.12-1).
[0985] The compounds in the following table (i.e. Examples 634 to
636) were prepared in the same manner as in Example 242 except that
the
4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}-1,4-
'-bipiperidine dihydrochloride was replaced with the corresponding
starting compound, or the 2 N sodium hydroxide aqueous solution was
replaced with methyl amine/methanol.
TABLE-US-00093 TABLE 93 Exam- Compound .sup.1H-NMR/ ple R.sup.3
R.sup.6 (R.sup.12-1) Name LC-MS, m/z 634 .sup.iPr H ##STR00662##
1-[3-(4-{3- [7-fluoro-3- (propan-2- yl)-1H- indazol-1- yl]-1,2,4-
oxadiazol- 5-yl} piperidin- 1-yl) azetidin- 1-yl]-2- hydroxy-
ethanone .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (6H, d, J = 7.1
Hz), 2.01- 2.29 (6H, m), 2.77-2.93 (2H, m), 3.04-3.17 (2H, m),
3.24- 3.34 (1H, m), 3.41-3.55 (1H, m), 3.91-4.02 (4H, m), 4.04-
4.19 (2H, m), 7.18-7.28 (2H, m), 7.56-7.62 (1H, m). LC-MS, m/z; 443
[M + H]+ 635 Et F ##STR00663## 1-{4-[3-(3- ethyl-6,7- difluoro-1H-
indazol-1- yl)-1,2,4- oxadiazol- 5-yl]-1,4'- bipiperidin- 1'-yl}-2-
hydroxy- ethanone .sup.1H-NMR (CDCl.sub.3) .delta.: 1.40- 1.58 (2H,
m), 1.43 (3H, t, J = 7.6 Hz), 1.83-1.95 (2H, m), 1.95-2.10 (2H, m),
2.14- 2.25 (2H, m), 2.34-2.47 (2H, m), 2.53-2.65 (1H, m), 2.68-
2.80 (1H, m), 2.90-3.10 (6H, m), 3.50-3.70 (2H, m), 4.16 (2H, s),
4.55- 4.68 (1H, m), 7.12-7.22 (1H, m), 7.42-7.49 (1H, m). LC-MS,
m/z; 475 [M + H]+ 636 Et H ##STR00664## 1-{4-[3-(3- ethyl-7-
fluoro-1H- indazol-1- yl)-1,2,4- oxadiazol- 5-yl]-3'- methyl-1,4'-
bipiperidin- 1'-yl}-2- hydroxy- ethnone .sup.1H-NMR (CDCl.sub.3)
.delta.: 0.86- 0.94 (3H, m), 1.36-1.57 (4H, m), 1.73-1.89 (2H, m),
1.93- 2.30 (7H, m), 2.52-2.82 (1H, m), 2.87-3.16 (6H, m), 3.27-
3.59 (1H, m), 3.66 (1H, br s), 4.01- 4.26 (2H, m), 4.40-4.72 (1H,
m), 7.17- 7.29 (2H, m), 7.49-7.56 (1H, m). LC-MS, m/z; 471 [M +
H]+
Example 637
Preparation of
1-(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}--
1,4'-bipiperidin-1'-yl)-2-hydroxyethanone (Form A and Form B)
##STR00665##
[0987] Form A:
1-(4-{3-[7-Fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}--
1,4'-bipiperidin-1'-yl)-2-hydroxyethanone prepared in Example 242
(33 g) was suspended in 2-propanol (45 mL), and then the suspension
was stirred at 85.degree. C. to dissolve the compound. The solution
was gradually cooled to room temperature, 2-propanol (9 mL) was
added thereto, and then the reaction mixture was stored in a
refrigerator for four days. The precipitated crystal was collected
on a filter, washed with cold 2-propanol, and then dried in vacuo
at 80.degree. C. to give the title compound (30.8 g) as a white
crystal which is characterized by the following X-ray diffraction
peaks.
XRD; 2.theta.=5.22, 10.42, 10.71, 11.16, 11.91, 12.71, 13.98,
14.61, 15.36, 15.64, 15.92, 16.83, 17.47, 18.27, 18.75, 19.46,
20.16, 20.56, 21.43, 21.74
[0988] Form B:
1-(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}--
1,4'-bipiperidin-1'-yl)-2-hydroxyethanone prepared in Example 242
(116 g) was suspended in 2-propanol (350 mL), and then the
suspension was stirred at 85.degree. C. to dissolve the compound.
The solution was gradually cooled to room temperature, and after
confirming that a crystal was precipitated, the mixture was stirred
at -10.degree. C. for two hours. The precipitated crystal was
collected on a filter, washed with cold 2-propanol (350 mL), and
then dried in vacuo at 60.degree. C. to give the title compound
(106 g) as a white crystal which is characterized by the following
X-ray diffraction peaks.
XRD; 2.theta.=8.00, 8.63, 9.87, 12.50, 13.58, 14.73, 15.07, 15.99,
16.39, 16.73, 17.73, 18.42, 19.38, 20.78, 21.31, 22.08, 22.48,
23.28, 23.63, 23.98
[0989] The X-ray diffraction (XRD) measurement was carried out
using X-ray diffraction system X' pert MPD (PANAlytical) under the
following condition:
[0990] Anode material: Copper,
[0991] K-Alpha1: 1.54 .ANG.,
[0992] Tension: 45 kV,
[0993] Current: 40 mA,
[0994] Start angle (2.theta.): 4.degree.,
[0995] End angle (2.theta.): 40.degree.,
[0996] Step size (2.theta.): 0.017.degree., and
[0997] Time per step: 100 s.
[0998] In detail, the measurement was carried out under the above
condition, using invisible Si plate as a sample assay plate which
was coated with about 5 mg of the sample. The X-ray diffraction
measurement of the samples mentioned below was also carried out as
the same.
Example 638
Preparation of
1-(4-{3-[7-fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol-5-yl}--
1,4'-bipiperidin-1'-yl)-2-hydroxyethanone hydrochloride
##STR00666##
[1000]
1-(4-{3-[7-Fluoro-3-(propan-2-yl)-1H-indazol-1-yl]-1,2,4-oxadiazol--
5-yl}-1,4'-bipiperidin-1'-yl)-2-hydroxyethanone prepared in Example
242 (2.44 g) was suspended in 2-propanol (36 ml) and ethanol (27
mL) and heated to 85.degree. C. to be dissolved. Then, 1N
HCl/diethyl ether (4.93 mL) was added thereto, and the mixture was
stirred at room temperature overnight. The precipitated crystal was
collected on a filter and suspended in 2-propanol (7 mL). The
suspension was heated at 85.degree. C. to dissolve the crystal, and
then the solution was gradually cooled to room temperature for
recrystallization. The resulting crystal was collected on a filter
to give the title compound (2.09 g) as a white crystal which is
characterized by the following X-ray diffraction peaks.
XRD; 2.theta.=5.28, 9.75, 10.55, 11.91, 12.47, 13.39, 14.63, 15.31,
15.69, 16.07, 16.37, 17.19, 17.82, 18.25, 18.63, 19.20, 19.51,
19.88, 20.69, 21.18
Examples 639 to 645
[1001] The following table shows the prepared compounds and X-ray
diffraction peaks thereof.
TABLE-US-00094 TABLE 94 Example Compound Name 2.theta. .sup.
639.sup.1) 1-{5-[1-(3- 7.97, 9.13, 10.55, 10.91,
methoxypropyl)piperidin-4- 11.94, 12.32, 12.91, 13.59,
yl]-1,2,4-oxadiazol-3-yl}-3- 14.90, 15.51, 15.98, 16.93,
(propan-2-yl)-1H-indazole 17.62, 17.86, 18.17, 18.70, hydrochloride
19.67, 20.15, 21.23, 21.86 (prepared in Example 85) 640
3-{4-[3-(3-ethyl-1H-indazol- 6.60, 10.99, 11.25, 12.38,
1-yl)-1,2,4-oxadiazol-5- 14.42, 15.12, 15.60, 16.34,
yl]piperidin-1-yl}propan-1-ol 16.84, 17.81, 19.78, 20.45, (prepared
in Example 261) 21.29, 21.88, 22.79, 23.19, 23.76, 24.64, 26.14 641
1-{4-[3-(3-ethyl-6-fluoro-1H 5.13, 9.93, 13.34, 13.68,
indazol-1-yl)-1,2,4- 15.50, 17.08, 17.62, 18.45,
oxadiazol-5-yl]-1,4'- 19.80, 19.96, 20.66, 21.14,
bipiperidin-1'-yl}ethanone 21.92, 22.29, 22.50, 23.15,
hydrochloride 24.28, 24.66, 26.25, 26.41 (prepared in Example 228)
642 1-{4-[3-(3-ethyl-7-fluoro-1H- 5.34, 8.57, 9.71, 10.58,
indazol-1-yl)-1,2,4- 11.36, 13.22, 13.66, 14.40,
oxadiazol-5-yl]-1,4'- 15.00, 15.58, 15.86, 16.30,
bipiperidin-1'-yl}ethanone 16.52, 16.96, 17.22, 17.84,
hydrochloride 18.20, 19.46, 20.28, 21.18, (prepared in Example 229)
21.62 643 methyl 4-[3-(3-ethyl-6- 5.90, 6.62, 9.93, 10.99,
fluoro-1H-indazol-1-yl)- 11.80, 12.06, 13.24, 15.18,
1,2,4-oxadiazol-5-yl]-1,4'- 16.76, 17.42, 18.11, 19.33,
bipiperidin-1'-carboxylate 20.16, 20.83, 21.14, 21.45, (prepared in
Example 230) 22.06, 22.36, 22.61, 23.68 644
1-(4-{3-[7-fluoro-3-(propan- 5.15, 9.54, 10.24, 13.02,
2-yl)-1H-indazol-1-yl]-1,2,4- 13.81, 15.11, 15.60, 16.10,
oxadiazol-5-yl}-1,4'- 16.74, 17.35, 18.32, 18.68,
bipiperidin-1'-yl)ethanone 19.10, 19.65, 19.90, 20.49,
hydrochloride 21.08, 22.04, 22.52, 23.35 (prepared in Example 232)
.sup. 645.sup.2) 1-(4-{3-[7-fluoro-3-(propan- 5.11, 10.20, 11.24,
11.78, 2-yl)-1H-indazol-1-yl]-1,2,4- 13.66, 14.10, 14.94, 15.30,
oxadiazol-5-yl}-1,4'- 15.62, 15.94, 16.32, 17.07,
bipiperidin-1'-yl)ethanone 17.38, 18.07, 18.74, 19.56, 20.34,
20.65, 21.27, 21.59, 22.65 .sup.1)prepared by treating the compound
prepared in Example 85 with 1N HCl/diethyl ether. .sup.2)prepared
in the same manner as in Example 637 from the free base compound
prepared in Example 232 provided that the conversion step into
hydrochloride was omitted.
Examples 646 to 650
##STR00667##
[1002] Wherein HX means the acid shown in the following table.
[1003] The salt compounds in the following table (i.e. Examples 646
to 650) were prepared in the same manner as in Example 638,
provided using the corresponding acid (HX) instead of HCl, solvent
and procedure shown in the following table. The equivalent of HX
shown in the following table means an equivalent thereof for the
free base compound which was used in the preparation process.
[1004] XRPD analyses were performed using a Rigaku MiniFlex II
Desktop X-Ray diffractometer using Cu radiation. The tube voltage
and amperage were set to 30 kV and 15 mA, respectively. The
scattering slit was fixed at 1.25.degree. and the receiving slit
was fixed at 0.3 mm. Diffracted radiation was detected by a NaI
scintillation detector. A 6-26 continuous scan at 1.0.degree./min
with a step size of 0.02-0.05.degree. from 3 to 45.degree. 26 was
used. Data were collected and analyzed using Jade 8.5.4. Each
sample was prepared for analysis by placing it in a low background,
round, 0.1 mm indent sample holder
TABLE-US-00095 TABLE 95 Example Salt (HX) Solvent(s) Procedure
2.theta. 646 Besylate Ethyl The freebase 4.30, 8.62, (1.05 acetate
(22.3 mg), 8.90, 9.92, eq.) acid, and 11.52, 12.70, solvent were
13.74, 16.00, heated to 17.15, 17.92, 70.degree. C., held 22.28,
23.86, for 1 hour, 25.26, 26.88 and cooled to room temperature 647
Besylate Ethyl Acid solution in IPA 4.32, 8.96, (1.35 acetate/ was
added to 9.96, 11.56, eq.) isopropanol freebase (387.8 mg) 12.76,
13.76, solution in 14.14, 14.98, IPA at 70.degree. C. then 15.76,
16.42, cooled to 0.degree. C. over 17.20, 17.96, 3 hours and held
18.46, 19.86, overnight (product 21.30, 21.74, oiled out). 22.30,
22.80, System was 23.12, 23.86 reheated to 60.degree. C., ethyl
acetate added, then cooled to 0.degree. C. over 2 hours. 425.8 mg
of salt was obtained. (0.8 mol counter acid: 1 mol free base) 648
Besylate 28 wt % Acid solution 4.44, 8.92, (0.97 methanol in in
ethyl acetate 9.14, 9.96, eq.) ethyl was added to 11.76, 13.34,
acetate freebase (350.9 mg) 14.16, 16.10, solution in ethyl 16.39,
17.88, acetate at 18.44, 19.42, 60.degree. C. then 20.56, 21.04,
cooled to 0.degree. C. over 21.42, 22.38, 80 minutes. 22.90, 23.70,
Heat this 25.34, 26.20, besylate salt (363.6 27.46, 28.50, mg) in
ethyl acetate 29.32, 30.32, to 67.degree. C. and 31.30, 32.60, add
enough 33.60, 34.51, methanol to 35.46 dissolve. Add acid solution
in ethyl acetate and cool to R.T. over 1 hour. 241.9 mg of salt was
obtained. (0.9 mol counter acid: 1 mol free base) 649 L- 10 vol %
Acid solution in 7.18, 10.84, tartrate methanol in methanol/ 11.52,
12.96, (1.09 ethyl ethyl acetate 14.36, 15.42, eq.) acetate was
added 16.12, 17.26, to freebase 17.62, 18.06, (387.5 mg) 18.96,
19.59, solution in 21.04, 21.88, methanol/ 24.52, 25.04, ethyl
acetate 26.16, 27.32, at 70.degree. C. 28.78, 29.71, then cooled to
30.56 20.degree. C. over 60 minutes. 483.5 mg of salt was obtained.
(1 mol counter acid: 1 mol free base) 650 Fumarate 15 vol % Salt
solution in 7.14, 7.68, (1.07 methanol in methanol/ 9.90, 12.74,
eq.) ethyl ethyl acetate 13.61, 14.36, acetate was added 14.65,
15.72, to freebase 17.36, 17.86, (351.3 mg) 19.74, 21.18, solution
in 21.62, 23.20, methanol/ 24.24, 25.08, ethyl acetate 26.20,
27.50, at 60.degree. C. then 28.90, 29.30, cooled to 31.18
0.degree. C. over 60 minutes. 4325.0 mg of salt was obtained. (1
mol counter acid: 1 mol free base)
(Pharmacological Test Result)
[1005] Hereinafter, some methods and results of the pharmacological
tests for the representative compounds of the present invention are
shown, but the present invention should not be construed as limited
to these pharmacological tests.
Test Example 1
Serotonin 4 (5-HT.sub.4) Receptor Binding Assay
[1006] The 5-HT.sub.4 receptor binding assay and preparations of
receptor membrane preparations herein were carried out according to
a method of Grossman et al. [see, British J. Pharmacol., (1993)
109, 618].
[1007] Slc-Hartley guinea pigs (body weight 300 g to 400 g) were
decapitated to remove brain rapidly, and striatum was isolated
which was cryopreserved at -80.degree. C. until use. To the
obtained tissues were added fifteen fold of Hepes buffer (50 mM, pH
7.4, 4.degree. C.), and the mixture was homogenized by Teflon
(trademark) homogenizer and centrifuged at 48,000.times.g
(4.degree. C.) for 15 minutes. To the resulting precipitate was
added Hepes buffer (1 ml) to 30 mg by wet weight of tissues, and
the mixture was suspended to give receptor membrane
preparations.
[1008] To an assay tube were added 0.1 nM [.sup.3H]-GR113808
{chemical name:
[1-[2-(methylsulfonylamino)ethyl]-4-piperidinyl]methyl
1-methylindole-3-carboxylate}, receptor membrane preparations, and
Hepes buffer (50 mM, pH 7.4, 4.degree. C., 1 ml) containing test
compounds or 30 .mu.M serotonin; and the mixture was incubated at
37.degree. C. for 30 minutes. On quenching the reaction, the
mixture was rapidly filtered on whatman GF/B filter, which was
presoaked in 0.1% polyethyleneimine for 1 hour, by using Brandel
cell Harvester, and washed with ice-cooled 50 mM Tris-HCl (pH 7.7,
4 ml) three times. To the filter after filtration was added a
liquid scintillator (Ecoscint), and then a radioactivity was
determined by a liquid scintillation counter.
[1009] 50% Inhibition concentrations (IC.sub.50) were determined
from inhibition rates of test compounds to specific bindings which
were obtained by subtracting nonspecific bindings from total
binding amounts of [.sup.3H]-GR113808.
[1010] Table 96 shows results of serotonin 4 (5-HT.sub.4) receptor
binding assay. In the following table, the compounds used in the
test are shown in numbers which correspond to the Example numbers
above where the preparations of the compounds are described. Each
IC.sub.50 shows the mean value of each group.
TABLE-US-00096 TABLE 96 Guinea pig 5-HT.sub.4 receptor binding
assay Example Number IC.sub.50 (nM) 85 31.1 87 21.0 88 33.5 92
<20 95 <20 98 32.1 101 <20 102 <20 103 <20 112 26.4
114 26.2 115 40.2 117 25.9 131 <20 132 <20 134 24.2 137
<20 138 <20 143 <20 171 31.9 178 <20 182 <20 195
<20 224 <20 228 28.7 229 <20 230 25.1 232 <20 242
<20 257 <20 261 <20 278 <20
Test Example 2
Serotonin 4 (5-HT.sub.4) Receptor Agonist Activity Assay
[1011] The cAMP measurement test used herein was carried out by
using CISBIO HTRF (trademark) cAMP Hirange kit according to the
manufacturer's instructions attached therewith.
[1012] CHO cells expressing human 5-HT.sub.4b receptor were
incubated in Medium 1 [DMEM/1% NEAA, 1% penicillin/streptomycin
(P/S), 0.2 mg/mL GENETICIN (G418), 10% FBS] at 37.degree. C. under
5% CO.sub.2 condition. Then, the cells were put into Medium 2
(DMEM/10000 cut FBS, G-418, P/S, NEAA) for 1 to 2 hours, and
collected by treating with trypsin containing EDTA. The collected
cells were suspended in Assay Buffer 1 [100 mM Hanks/HEPES buffer
(pH 7.4)], the suspended cells were mixed with the testing compound
on 384-well plates, and the cells were incubated at 31.degree. C.
for 15 minutes. To the cells were added cAMP-cryptate solution and
cAMP-d.sub.2 solution, and they were incubated at room temperature
for 1 hour. Then, time-resolved fluorescence was measured by En
Vision (excitation wavelength: 330 nm, fluorescence wavelength:
620/665 nm). An intrinsic activity of the compound [IA (%)] and a
concentration showing 50% of IA [EC.sub.50 (nM)] were calculated
from the obtained results. In particular, the intrinsic activity
(IA) was calculated on the basis of the maximal activity of 5-HT
(measured from 10.sup.-11 M to 10.sup.-7 M) defined as 100%.
[1013] Table 97 shows results of serotonin 4 (5-HT.sub.4) receptor
agonist activity assay. In the following table, the compounds used
in the test are shown in numbers which correspond to the Example
numbers above where the preparations of the compounds are
described. Each IA and EC.sub.50 shows the mean value of each
group.
TABLE-US-00097 TABLE 97 Example Number IA (%) EC.sub.50 (nM) 85 125
8.3 87 80 9.4 88 37 16.4 92 92 6.5 95 43 3.7 98 110 15.5 101 70 8.9
102 26 8.0 103 59 11.0 112 73 24.9 114 68 53.0 115 58 153 117 83
29.5 131 77 9.3 132 29 14.7 134 81 12.1 137 66 8.6 138 67 22.4 143
81 6.0 171 51 30.8 178 38 10.9 182 38 4.0 195 49 31.4 228 66 8.2
229 55 2.9 230 65 17.9 232 95 2.6 242 88 2.2 257 48 60.7 261 84
6.2
Test Example 3
Serotonin 4 (5-HT.sub.4) Receptor Binding Assay
[1014] The guinea pig 5-HT.sub.4 receptor binding assay and
preparations of receptor membrane preparations herein were carried
out according to a method of Grossman et al. [see, British J.
Pharmacol., (1993) 109, 618].
[1015] Slc-Hartley guinea pigs (body weight 300 g to 400 g) were
decapitated to remove brain rapidly, and striatum was isolated
which was cryopreserved at -80.degree. C. until use. To the
obtained tissues were added fifteen fold of Hepes buffer (50 mM, pH
7.4, 4.degree. C.), and the mixture was homogenized by Teflon
(trademark) homogenizer and centrifuged at 48,000.times.g
(4.degree. C.) for 15 minutes. To the resulting precipitate was
added Hepes buffer (1 ml) to 30 mg by wet weight of tissues, and
the mixture was suspended to give receptor membrane
preparations.
[1016] To an assay tube were added 0.1 nM [.sup.3H]-GR113808
{chemical name: [1-[2-(methylsulfonylamino)
ethyl]-4-piperidinyl]methyl 1-methylindole-3-carboxylate}, receptor
membrane preparations, and Hepes buffer (50 mM, pH 7.4, 4.degree.
C., 1 ml) containing test compounds or 30 .mu.M serotonin; and the
mixture was incubated at 37.degree. C. for 30 minutes. On quenching
the reaction, the mixture was rapidly filtered on whatman GF/B
filter, which was presoaked in 0.1% polyethyleneimine for 1 hour,
by using Brandel cell Harvester, and washed with ice-cooled 50 mM
Tris-HCl (pH 7.7, 4 ml) three times. To the filter after filtration
was added a liquid scintillator (Ecoscint), and then a
radioactivity was determined by a liquid scintillation counter.
[1017] 50% Inhibition concentrations (IC.sub.50) were determined
from inhibition rates of test compounds to specific bindings which
were obtained by subtracting nonspecific bindings from total
binding amounts of [.sup.3H]-GR113808.
[1018] Human 5-HT.sub.4 receptor membrane preparations were
prepared from CHO-K.sup.1 cells which stably express 5-HT4b
receptors, and human 5-HT.sub.4 receptor binding assay was carried
out in a similar manner as in the guinea pig 5-HT.sub.4 receptor
binding assay. The following tables show results of serotonin 4
(5-HT.sub.4) receptor binding assay. In the following tables, the
compounds used in the test are shown in numbers which correspond to
the Example numbers above where the preparations of the compounds
are described. Each IC.sub.50 shows the mean value of each
group.
TABLE-US-00098 TABLE 98 Guinea pig 5-HT.sub.4 receptor binding
assay Ex. IC.sub.50 No. (nM) 201 <20 202 <20 203 <20 209
<20 210 <20 216 <20 219 <20 220 <20 221 <20 223
<20 224 <20 233 <20 237 <20 241 <20 244 <20 246
<20 247 <20 250 <20 394 <20 395 26.9 396 <20 397
<20 398 <20 402 <20 403 36.1 404 100 405 65.4 406 68.7 407
101 408 29.5 409 383 410 323 412 140 413 <20 414 86.9 415 <20
417 36 420 73.9 421 129 422 55 427 339 428 248 431 130 433 65 434
20.8 435 44.7 436 179 437 113 440 104 441 78.2 442 <20 443 18.1
445 <20 446 <20 447 <20 448 <20 449 <20 450 <20
451 <20 452 <20 453 28.1 454 <20 455 <20 456 <20 457
85.3 458 66 459 <20 460 <20 461 <20 462 109 463 <20 464
<20 465 <20 466 <20 467 81.1 468 <20 469 20.4 470 30
471 173 472 29.7 473 23.8 474 20.2 475 67.9 476 <20 477 <20
478 <20 479 94.6 480 27.5 481 <20 482 23.6 483 35.7 484 28.1
485 21.2 486 <20 495 <20 507 <20 519 27.1 520 <20 521
93.7 522 222 529 <20 530 <20 532 <20 533 <20 551 81.9
552 179 553 18.7 554 190 555 24.9 557 127 562 478 563 222 564
653
TABLE-US-00099 TABLE 99 Human 5-HT.sub.4 receptor binding assay Ex.
IC.sub.50 No. (nM) 232 <20 242 <20 399 20.2 400 225 401 296
416 27.4 418 442 419 63.8 423 136 424 55 444 96.8 487 <20 488
<20 489 <20 490 <20 491 <20 492 <20 493 <20 494
<20 496 <20 497 76.1 498 <20 499 48.6 500 <20 501
<20 502 <20 503 <20 504 <20 505 <20 506 <20 508
<20 509 27.4 510 <20 511 <20 512 <20 513 <20 514
<20 515 <20 516 <20 517 <20 518 <20 523 <20 524
<20 525 <20 526 25.2 527 <20 528 <20 531 <20 534
42.4 535 29.7 536 <20 537 <20 538 <20 539 <20 540 78.1
541 35.8 542 <20 543 <20 544 <20 545 <20 546 <20 547
<20 548 <20 549 <20 550 <20 556 52.1 558 <20 559
<20 561 33.3 566 <20 582 <20 583 <20 585 <20 586
<20 590 12.6 591 <20 592 <20 593 <20 594 <20 595
<20 596 <20 597 26.9 598 <20 599 <20 600 <20 601
<20 602 <20 603 28.6 604 <20 605 <20 606 86.7 607
<20 608 <20 609 <20 610 <20 611 95.9 612 20.5 613
<20 614 <20 615 27.4 616 <20 617 24.3 618 <20 619 39.2
620 <20 621 69.4 622 123 623 105 624 <20
Test Example 4
Serotonin 4 (5-HT.sub.4) Receptor Agonist Activity Assay
[1019] The cAMP measurement test used herein was carried out by
using CISBIO HTRF (trademark) cAMP Hirange kit according to the
manufacturer's instructions attached therewith.
[1020] CHO cells expressing human 5-HT.sub.4b receptor were
incubated in Medium 1 [DMEM/1% NEAA, 1% penicillin/streptomycin
(P/S), 0.2 mg/mL GENETICIN (G418), 10% FBS] at 37.degree. C. under
5% CO.sub.2 condition. Then, the cells were put into Medium 2
(DMEM/10000 cut FBS, G-418, P/S, NEAA) for 1 to 2 hours, and
collected by treating with trypsin containing EDTA. The collected
cells were suspended in Assay Buffer 1 [100 mM Hanks/HEPES buffer
(pH 7.4)], the suspended cells were mixed with the testing compound
on 384-well plates, and the cells were incubated at 31.degree. C.
for 15 minutes. To the cells were added cAMP-cryptate solution and
cAMP-d.sub.2 solution, and they were incubated at room temperature
for 1 hour. Then, time-resolved fluorescence was measured by En
Vision (excitation wavelength: 330 nm, fluorescence wavelength:
620/665 nm).
[1021] An intrinsic activity of the compound [IA (%)] and a
concentration showing 50% of IA [EC.sub.50 (nM)] were calculated
from the obtained results. In particular, the intrinsic activity
(IA) was calculated on the basis of the maximal activity of 5-HT
(measured from 10.sup.-11 M to 10.sup.-7 M) defined as 100%.
[1022] Table 100 shows results of serotonin 4 (5-HT.sub.4) receptor
agonist activity assay. In the following table, the compounds used
in the test are shown in numbers which correspond to the Example
numbers above where the preparations of the compounds are
described. Each IA and EC.sub.50 shows the mean value of each
group.
TABLE-US-00100 TABLE 100 Ex. EC.sub.50 No. IA (%) (nM) 201 39.7 6.8
202 39.0 5.8 203 71.8 1.1 209 79.1 3.7 210 68.6 5.0 216 62.3 4.6
219 96.9 2.8 220 92.4 4.8 221 86.1 6.1 223 72.7 3.4 224 73.9 6.7
233 93.5 2.9 237 51.9 9.7 241 58.8 3.2 244 63.5 3.9 246 56.6 21.1
247 79.0 12.7 250 79.7 3.5 394 101.0 3.1 402 106.0 1.8 405 21.6
34.2 419 110.0 10.4 420 85.6 8.2 435 1.6 11.9 445 52.1 13.2 447
56.8 12.2 448 57.5 8.9 449 76.4 31.2 450 87.7 15.8 451 83.1 13.8
455 99.0 28.1 457 72.2 12.7 458 85.4 2.7 459 68.2 7.6 460 78.6 5.3
461 65.5 4.4 463 64.4 8.3 464 70.0 31.2 467 72.5 6.9 468 69.8 22.4
469 68.8 5.3 470 70.4 13.4 472 54.3 47.2 473 58.5 23.1 474 89.4
34.4 475 61.0 13.6 477 65.5 11.4 478 68.7 32.4 481 73.8 7.1 482
70.5 8.9 487 70.0 3.2 488 106.0 2.9 489 104.0 2.5 490 111.0 1.6 491
91.0 4.4 492 78.0 2.9 493 75.0 1.5 494 72.0 2.1 496 70.0 2.2 497
88.0 5.8 498 36.0 3.4 499 82.0 7.8 500 90.0 14.4 501 84.0 3.5 502
70.0 3.5 503 98.0 5.0 504 47.0 3.9 505 52.0 5.5 506 46.0 2.8 507
84.0 3.9 508 54.0 3.7 509 56.0 16.3 510 46.0 2.7 511 51.0 9.6 512
30.0 4.3 513 81.0 10.2 514 70.0 12.0 515 70.0 8.5 516 75.0 7.2 517
72.0 6.1 518 59.0 5.5 519 81.1 33.5 520 82.9 17.6 523 24.0 2.9 524
84.0 4.3 525 86.0 18.1 527 114.0 5.7 528 121.0 17.3 529 95.5 1.2
530 97.0 3.1 531 95.0 11.4 532 99.0 5.0 533 102.0 3.8 534 104.0 5.7
536 100.0 3.7 537 111.0 1.3 538 76.0 2.4 539 75.0 2.6 540 106.0
15.3 541 79.0 9.0 542 90.0 3.3 543 92.0 3.7 544 58.0 4.7 545 60.0
5.5 546 63.0 20.1 547 54.0 14.1 548 73.0 6.4 549 91.0 5.6 550 85.0
5.1 551 70.4 18.5 558 109.0 1.0 559 81.0 3.0 561 109.0 8.9 566 90.0
3.1 582 91.0 3.7 583 84.0 5.9 585 109.0 2.4 586 105.0 2.2 590 101.0
2.8 591 97.0 2.6 593 99.0 2.7 594 106.0 2.3 595 93.0 6.9 596 82.0
4.1 605 113.0 2.3 610 103.0 9.1 611 94.0 42.2 612 82.0 14.6 614
93.0 10.9 616 105.0 13.0 617 104.0 8.4 618 32.0 6.2
Example 5
The Effect of Compounds on Scopolamine-Treated Cognitive
Impairment
[1023] Scopolamine, a muscarinic antagonist, significantly impairs
cognition by blocking acetylcholine transmission. Thus,
scopolamine-induced cognitive impairment model, one of the AD-like
model, has been used to predict pharmacodynamic signals of putative
procognitive compounds, utilizing the acetylcholinesterase
inhibitor donepezil for illustration (See, Citations 1 and 2). The
present inventors investigated the effect of each compound on
reversal of scopolamine-induced deficits in performance of Y-maze
test in mice, and they also investigated adjunctive effect of
compounds with donepezil on reversal of deficits induced by
scopolamine and MK801 in mice.
[1024] Used animal: ddY mouse (SLC)
Grouping of Animals
[1025] In the experiments, the mice were grouped in the same way
using Stat Preclinica (Version 1.03295; Takumi Information
Technology Inc.). The selected mice were divided into 5 to 7 groups
of 7 to 12 mice using the "completely randomization design by the
single variable" program (Analytical program version 1.0.7), with
body weight on the testing day. After grouping, p values for
Bartlett's test and ANOVA across all groups were greater than 0.2,
indicating no significant difference in this parameter among the
groups.
Dosing Method and Schedule
[1026] The required amount of each compound was weighed and put
into a glass homogenizer. The required amount of 0.5% MC (methyl
cellulose) solution was added, and each compound was suspended to
give a 10 mg/kg dosing suspension.
[1027] The required amount of donepezil was weighed and put into a
glass homogenizer. The required amount of 0.5% MC solution was
added, and donepezil was suspended to give a suspension at
concentration of 1 mg/mL (10 mg/kg dosing suspension).
[1028] The required amount of scopolamine and MK801 were weighed,
and saline was added to it to give 0.3 mg/mL and 0.015 mg/mL
solution, respectively.
[1029] 90 Min before the test, the mice were orally administered
each compound, donepezil, and vehicle (0.5% methyl cellulose, 10
mL/kg). After 60 min, memory impairment was induced by
administering scopolamine (0.6 mg/kg, s.c.) with
(co-administration) or without (mono-administration) MK801 (0.03
mg/kg, s.c.). The control group received saline (2 mL/kg, s.c.)
rather than scopolamine and MK801.
Y-maze test
[1030] The Y-maze used herein is a three-arm maze with equal angles
between all arms. The mazefloor and walls were constructed from
black acrylic resin. The mice were initially placed within one arm,
and the sequence and number of arm entries were recorded manually
for each mouse over an 8-min period.
[1031] Data were processed and analyzed with Microsoft.RTM. Office
Excel 2003. The alternation behavior was defined as entries into
all three arms on consecutive occasions. The percent alternation
behavior in each animal was calculated using the following formula,
and rounded to one decimal place.
Alternation behavior(%)=[actual alternation/(total arm
entries-2)].times.100
[1032] Restoration ratio of alternation behavior (%) in each animal
was calculated using the following formula, and rounded to one
decimal place.
y=100.times.(x-B)/(A-B)
Restoration ratio of alternation behavior in each animal (%)=y
Alternation behavior in each animal (%)=x Mean of alternation
behavior in vehicle-treated group (group No. 1) (%)=A Mean of
alternation behavior in scopolamine-treated group (group No. 2)
(%)=B
[1033] Data were expressed as the mean of the percent alternation
behavior, the number of total arm entries and the restoration ratio
of alternation behavior.
Definition of Cognitive Impairment Induced by Scopolamine and
MK801
[1034] Values of Y-maze tests are expressed as mean of alternation
behavior (n=7-12).
[1035] Alternation behaviors in the scopolamine-treated groups were
compared to those in the control groups using Wilcoxon rank sum
test (Stat preclinical; Version 1.03295; Takumi Information
Technology Inc.) with a two-sided significance level of 0.05.
Statistical significance in the scopolamine-treated group compared
with the control group (*P<0.05) exhibits cognitive
impairment.
The Effect of Each Compound on Scopolamine Induced Cognitive
Impairment
[1036] Restoration of alternation behavior was analyzed using Stat
Preclinica. Alternation behaviors in the vehicle-treated group were
compared to those in the test substance-treated groups using
non-parametric Dunnett multiple comparison test (Analytical program
version 1.0.2) with a two-sided significance level of 0.05.
Statistical significance in the test substance-treated group
compared with the scopolamine-treated group (#P<0.05) exhibits
reversal of scopolamine-induced deficits in cognition.
The Effect of Co-Administration of Compound 232 and Compound 242
Together with the Acetylcholinesterase Inhibitor Donepezil on
Scopolamine Induced Cognitive Impairment
[1037] Restoration of alternation behavior was analyzed using Stat
Preclinica. Alternation behaviors in the Donepezil (10 mg/kg,
p.o.)-treated group were compared to those in the co-administrated
groups of test compounds with donepezil (10 mg/kg, p.o.) using
non-parametric Dunnett multiple comparison test (Analytical program
version 1.0.2) with a two-sided significance level of 0.05.
Statistical significance in the co-administered group compared with
the donepezil-treated group ($P<0.05) shows that the
co-administration increases reversal of cognitive impairment
compared with the administration of donepezil alone in scopolamine
and MK801-induced deficits.
CITATIONS
[1038] (1) Knox L T, Jing Y, Fleete M S, Collie N D, Zhang H, Liu
P. Scopolamine impairs behavioural function and arginine metabolism
in the rat dentate gyrus. Neuropharmacology 2011; 61: 1452-62.
[1039] (2) Ogura H, Kosasa T, Araki S, Yamanishi Y. Pharmacological
properties of donepezil hydrochloride (Aricept.RTM.), a drug for
Alzheimer's disease. Folia Pharmacol Jpn 2000; 115: 45-51. [1040]
(3) Kwon S H, Kim H C, Lee S Y, Jang C G. Loganin improves learning
and memory impairments induced by scopolamine in mice. Eur J
Pharmacol 2009; 619: 44-9.
[1041] The effect of each compound on scopolamine-induced cognitive
impairment is shown in Table 101.
[1042] The effect of co-administration of compound 232 and 242 with
donepezil is shown in Table 102.
TABLE-US-00101 TABLE 101 Single-agent administration compound
(mg/kg, p.o.) normal control 1 3 10 Example 205 (n = 9) scopolamine
- + + + + vehicle + + - - - Alternation behavior (%) 77.0 49.1*
66.9.sup.# 54.8 66.7.sup.# Example 218 (n = 9) scopolamine - + + +
+ vehicle + + - - - Alternation behavior (%) 77.0 49.1* 59.9 53
61.3 Example 137 (n = 11 to 12) scopolamine - + + + + vehicle + + -
- - Alternation behavior (%) 69.7 49.2* no 49.3 62.6.sup.# data
Example 232 (n = 8 to 10) scopolamine - + + + + vehicle + + - - -
Alternation behavior (%) 74.1 48.4* 66.3.sup.# 63.0.sup.# 53.6
Example 242 (n = 7 to 10) scopolamine - + + + + vehicle + + - - -
Alternation behavior (%) 68.9 44.4* 63.4.sup.# 62.9.sup.# 57.5
*Statistical significance in the scopolamine-treated group compared
with the control group using Wilcoxon rank sum test (with a
two-sided significance level of 0.05). .sup.#Statistical
significance in the test substance-treated group compared with the
scopolamine-treated group using non-parametric Dunnett multiple
comparison test (Analytical program version 1.0.2) with a two-sided
significance level of 0.05.
TABLE-US-00102 TABLE 102 Co-administration with donepezil Example
232 nor- Donepezil compound (mg/kg, p.o.) (n = 11 to 12) mal
control 10 mg/kg 0.03 0.1 0.03 0.1 scopolamine + - + + + + + +
MK801 vehicle + + - - - - - Donepezil - - + - - + + (10 mg/kg,
p.o.) Alternation 67.4 44.1* 51.5.sup.# 46.7 48.0.sup.# 48.5
62.4.sup.$ behavior (%) Example 242 nor- Donepezil compound (mg/kg,
p.o.) (n = 8) mal control 10 mg/kg 0.1 0.3 0.1 0.3 scopolamine + -
+ + + + + + MK801 vehicle + + - - - - - Donepezil - - + - - + + (10
mg/kg, p.o.) Alternation 69.7 38.2* 49.9.sup.# 51.2.sup.#
57.4.sup.# 58.6.sup.$ 62.5.sup.$ behavior (%) *Statistical
significance in the scopolamine-treated group compared with the
control group using Wilcoxon rank sum test with a two-sided
significance level of 0.05. .sup.#Statistical significance in the
test substance-treated group compared with the scopolamine-treated
group using non-parametric Dunnett multiple comparison test with a
two-sided significance level of 0.05. .sup.$Statistical
significance in the co-treated (donepezil and test compounds) group
compared with the donepezil (10 mg/kg)-treated group using
non-parametric Dunnett multiple comparison test with a two-sided
significance level of 0.05.
INDICATION
[1043] The present inventions are applied to, for example, treating
or preventing the diseases or symptoms of the following (i) to
(v):
(i) neuropsychiatric diseases such as Alzheimer-type dementia, Lewy
body dementia, vascular dementia, depression, posttraumatic stress
disorder (PTSD), memory impairment, anxiety, and schizophrenia;
(ii) digestive system diseases such as irritable bowel syndrome,
atonic constipation, habitual constipation, chronic constipation,
constipation induced by drugs (e.g. morphine and antipsychotic
drugs), constipation associated with Parkinson's disease,
constipation associated with multiple sclerosis, constipation
associated with diabetes mellitus, and constipation or dyschezia
caused by contrast materials taken as a pretreatment for endoscopic
examinations or barium enema X-ray examinations; (iii) digestive
system diseases such as functional dyspepsia, acute/chronic
gastritis, reflux esophagitis, gastric ulcer, duodenal ulcer,
gastric neurosis, postoperative paralytic ileus, senile ileus,
non-erosive reflux disease, NSAID ulcer, diabetic gastroparesis,
postgastrectomy syndrome, and intestinal pseudo-obstruction; (iv)
digestive system symptoms such as the digestive system diseases
mentioned in the above (ii) and (iii), scleroderma, diabetes
mellitus, anorexia in esophageal/biliary-tract diseases, nausea,
emesis, bloating, epigastric discomfort, abdominal pain, heartburn,
and belching; and (v) urinary system diseases associated with
dysuria such as urinary tract obstruction and prostatic
hyperplasia.
[1044] Thus, the present compounds can be used for treating and
preventing the various diseases mentioned above (in particular,
neuropsychiatric diseases) and abnormal-functions of digestive
system associated with the treatment of the various diseases
mentioned above and the like. In specific, the present compound is
useful as a medicament for treating especially the neuropsychiatric
diseases such as Alzheimer-type dementia mentioned in the above (i)
because the compound shows an excellent 5-HT4 receptor agonist
activity and brain penetration.
[1045] In addition, the present compound is expected to show
further efficacy in treating the various neuropsychiatric diseases
mentioned in the above (i), especially Alzheimer-type dementia, by
combining at least one of the following medicaments:
acetylcholinesterase inhibitors such as donepezil, galantamine,
rivastigmine, SNX-001 and NP-61; cholinesterase inhibitors such as
huperzine A; NMDA receptor antagonists such as memantine, dimebon
and neramexane; 5-HT6 receptor antagonists such as PF-5212365
(SAM-531), SB-742457, LU-AE58054, AVN-322, PF-05212377 (SAM-760)
and AVN101; .alpha.7nAChR agonists such as TC-5619, EVP-6124 and
GTS-21; .alpha.4.beta.2nACh receptor agonists such as AZD-1446 and
CHANTIX (varenicline); nAChR agonists such as ABT-089; AMPA
receptor agonists such as CX-717 and LY-451395; histamine H3
antagonists such as ABT-288, SAR-110894 and PF-03654746; muscarinic
M1 receptor agonists such as MCD-386 and GSK-1034702; PDE4
inhibitors such as etazolate; PDE9 inhibitors such as PF-04447943;
histone deacetylase inhibitors such as EVP-0334; .sigma.1 receptor
agonists such as Anavex-2-73; .gamma.-secretase inhibitors (GSI)
such as BMS-708163, NIC5-15, ELND-006, and MK-0752;
.gamma.-secretase modulators (GSM) such as E-2212 and CHF-5074;
A.beta. human monoclonal antibodies such as bapineuzumab,
solanezumab, PF-4360365 (ponezumab), gantenerumab (R-1450),
BAN-2401, MABT-5102A, RG-7412 and GSK-933776A; A.beta. vaccines
such as ACC-001 (PF-05236806), AD-02, CAD-106, V-950, UB-311 and
ACI-24; human immunoglobulins such as GAMMAGARD; Ap aggregation
inhibitors such as ELND-005 (AZD-103), PBT-2, NRM-8499 and
Exebryl-1; tau aggregation inhibitors such as TRx-0014 and LMTX;
RACE inhibitors such as ACI-91, posiphen, CTS-21166, HPP-854 and
LY-2886721; tyrosine kinase inhibitors such as masitinib;
GSK-3.beta. inhibitors/tau kinase inhibitors such as NP-12; RAGE
fusion proteins such as TTP-4000; ApoA-I/HDL-C elevations such as
RVX-208; other various agents showing neuroprotective action such
as SK-PC-B70M, T-817MA, davunetide, HF-0220, PF-4494700, PYM-50028,
CERE-110, ASP-0777, TAK-065, and AAD-2004; and other medicaments
used for treating various types of dementia.
INDUSTRIAL APPLICABILITY
[1046] The present compound is useful as a medicament for treating
or preventing diseases or symptoms associated with serotonin-4
receptor. The diseases or symptoms suggested to be associated with
serotonin-4 receptor include the following (i) to (v):
(i) neuropsychiatric diseases such as Alzheimer-type dementia, Lewy
body dementia, vascular dementia, depression, posttraumatic stress
disorder (PTSD), memory impairment, anxiety, and schizophrenia;
(ii) digestive system diseases such as irritable bowel syndrome,
atonic constipation, habitual constipation, chronic constipation,
constipation induced by drugs (e.g. morphine and antipsychotic
drugs), constipation associated with Parkinson's disease,
constipation associated with multiple sclerosis, constipation
associated with diabetes mellitus, and constipation or dyschezia
caused by contrast materials taken as a pretreatment for endoscopic
examinations or barium enema X-ray examinations; (iii) digestive
system diseases such as functional dyspepsia, acute/chronic
gastritis, reflux esophagitis, gastric ulcer, duodenal ulcer,
gastric neurosis, postoperative paralytic ileus, senile ileus,
non-erosive reflux disease, NSAID ulcer, diabetic gastroparesis,
postgastrectomy syndrome, and intestinal pseudo-obstruction; (iv)
digestive system symptoms such as the digestive system diseases
mentioned in the above (ii) and (iii), scleroderma, diabetes
mellitus, anorexia in esophageal/biliary-tract diseases, nausea,
emesis, bloating, epigastric discomfort, abdominal pain, heartburn,
and belching; and (v) urinary system diseases associated with
dysuria such as urinary tract obstruction and prostatic
hyperplasia.
[1047] In addition, the present compound is useful as a medicament
for treating or preventing especially the neuropsychiatric diseases
such as Alzheimer-type dementia mentioned in the above (i) because
the compound shows an excellent 5-HT4 receptor agonist activity and
brain penetration.
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